|MAT LADE MORA TUTTA USLA 20170239307A1 LA LA LA MATATANI MATA ( 19) United States (12 ) Patent Application Publication ( 10) Pub . No. : US 2017/ 0239307 A1 Villegas Becerril (43 ) Pub . Date : Aug. 24 , 2017

(54 ) COMPOSITION OF DOXYCYCLINE IN (30 ) Foreign Application Priority Data LIPOSOMES FOR THE PREVENTION , IMPROVEMENT AND /OR TREATMENT OF Sep . 23 , 2014 (ES ) ...... P201431379 OCULAR PATHOLOGIES Dec . 16 , 2014 ( ES ) ...... P201431854 Publication Classification (71 ) Applicant: AGENCIA PÚBLICA (51 ) Int. CI. EMPRESARIAL SANITARIA A61K 36 /53 (2006 .01 ) HOSPITAL ALTO A61K 36 / 28 ( 2006 . 01 ) GUADALQUIVIR , Jaén (ES ) A61K 36 /886 ( 2006 . 01 ) A61K 9 /00 (2006 . 01) (72 ) Inventor : Enrique Villegas Becerril, Jaén ( ES ) (52 ) U . S . CI. CPC ...... A61K 36 /53 (2013 . 01 ) ; A61K 9 /0048 (21 ) Appl . No .: 15 /513 , 493 (2013 . 01 ); A61K 36 /28 (2013 .01 ) ; A61K 36 / 886 ( 2013. 01 ) ( 22 ) PCT Filed : Sep . 23 , 2015 ( 57 ) ABSTRACT The invention relates to use of a composition comprising (86 ) PCT No. : PCT/ ES2015 /070695 doxycycline in the production of a topically administered $ 371 ( c ) ( 1 ), medicament for the prevention , improvement and / or treat (2 ) Date : Mar. 22 , 2017 ment of ocular disorders . Patent Application Publication Aug . 24 , 2017 Sheet 1 of 6 US 2017 /0239307 A1

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COMPOSITION OF DOXYCYCLINE IN have already used topical doxycycline for the treatment of LIPOSOMES FOR THE PREVENTION , dry eye , although it has never been used for blepharitis IMPROVEMENT AND /OR TREATMENT OF treatment. OCULAR PATHOLOGIES 0007 ] Doxycycline has anti - infection effect and anti- in flammatory effect ( Wang et al ., 2008. Clin . Experiment. FIELD OF THE INVENTION Ophthalmol. 36 ( 1 ) , 8 - 12 ; Dursun et al. , 2008 . Am . J . Oph thalmol. 132 ( 1 ) , 8 - 13 ) . The amount of orally administered [0001 ] The present invention is comprised in the field of tetracycline may not reach sufficient concentration in the biology and medicine and relates to the use of doxycycline tear film where it exerts its function ( Smith et al. , 2008 . Br. for the prevention , improvement and / or treatment of ocular J. Ophthalmol. 92( 6 ), 856 - 859) . disorders . Preferably, the present invention relates to the [0008 ] Doxycycline has a protective effect on the walls of topical use of doxycycline in liposomes in the form of stable the microvasculature . In fact, it is used in the prevention of eye drops for the prevention , improvement and / or treatment aortic aneurysms through the inhibition of enzymes degrad of blepharitis , microthrombosis in the anterior pole and ing vessel walls. In certain groups of hemodialysis patients , chorioretinal vascular disorders . doxycycline proved to be effective in the prevention of thrombosis (Diskin et al ., 1998 . Nephron 78 , 365 - 368; Saran BACKGROUND OF THE INVENTION et al. , 2002. Am . J . Kidney Dis . 40 , 1255 - 1263 ) . [0009 ] The protective effect of doxycycline on the vessel [0002 ] Blepharitis is one of the most common ophthalmo wall seems to be determined by metalloproteinase matrix logical diseases . It represents a wide range of acute and activity inhibition ( Sorsa et al. , 1994 . Ann . NY. Acad . Sci. chronic diseases characterized by inflammation of the free 732 , 375 -378 ) . margin of the eyelid . For both patients and ophthalmolo [0010 ] In a study conducted on rats , doxycycline was gists , this disease is very hard to understand , frustrating due capable of preventing aneurysmal dilatation without subse to its chronic nature and extremely tedious as a result of the quent signs of inflammation (Kaito et al. , 2003 . Surg. Today prolonged treatment it requires . 33, 426 -433 ) . In other work , patients taking doxycycline 10003 ] The free margin of the eyelid is the source of were found to have less vascular intimal layer proliferation inflammation which spreads to the cornea and bulbar con as well as less muscle cell migration ( Islam et al ., 2003 . Am . junctiva . This means that different types of patients are J. Pathol. 163 , 1557 -1566 ). observed : patients with bulbar conjunctival vessel conges [0011 ] The physiopathology of diabetic retinopathy ( DR ) tion , with infiltration of the cornea and conjunctiva adnexa has yet to be fully clarified , but most authors attribute it to and pannus (vessel invasion into the peripheral cornea ) , vascular changes . In contrast , it has been recently discovered particularly in the inferior cornea . that there are changes in the glia and on a neuronal level that [ 0004 ] It is important to know the different manifestations may explain part of this physiopathology . ( Antonetti et al. , of blepharitis in order to apply suitable treatment (Raskin et 2012. N . Engl. J. Med . 366 ( 13 ) , 1227 - 1239 ) . Chronic al. , 1992 . Infect. Dis . Clin . North Am . 6 ( 4 ) , 777 -787 ) . More inflammatory changes occurring in DR in experimental than 80 agents responsible for blepharitis have been identi models include increased local nitric oxide production , fied ( Ostler, 1993 . Diseases of the external eye and adnexa , increased intracellular molecular adhesion , leukostasis and Baltimore , Williiams and Wilkins) , the most common ones increased cell expression by means of cytokines which are are Streptococus, Staphilococus, Pseudomonas, Moraxella in turn associated with tissue damage and neuronal damage and Actinomices , in addition to other not so common ones and loss ( Adamis et al. , 2008 . Semin . Immunopathol. 30 ( 2 ) , such as Anthrax , Pasteurella , Clostridium and Micobaste 65 -84 ; Tang et al ., 2011. Prog . Retin . Eye Res. 30 (5 ), rium tuberculosis (Groden et al. , 1991. Cornea 10 ( 1 ) , 343 -358 ) . 50 - 53 ) . There are also other agents of viral origin (Mollus [0012 ] The microglia represents the first line of the cum contagiosum , Herpes simplex and Herpes zoster ) and immune system against attacks and usually remains inactive , fungi ( Coccidioides, Microsporum blastomices, Candida but in situations such as DR it is activated , inducing inflam and Aspergillus ) . Furthermore, there are also allergic disor matory changes (Rungger - Brändle et al. , 2000 . Invest . Oph ders ( atopy and contact dermatitis ) and other Steven - John thalmol. Vis Sci. 41 ( 7 ) , 1971 - 1980 ; Zeng et al. , 2000 . Vis son - type syndromes, ichthyosis or Lyell ’ s syndrome. Neurosci . 17 (3 ), 463 -471 ; Zeng et al. , 2008. Arch . Ophthal [ 0005 ] There are currently four blepharitis treatment alter mol. 126 ( 2 ) , 227 - 232 ; Barber et al ., 2005 . Invest Ophthalmol natives: eyelid hygiene , topical antibiotics, systemic antibi Vis Sci. 46 ( 6 ), 2210 - 2218 ; Gaucher et al. , 2007 . Vision Res . otics such as tetracyclines (Neiberg and Sowka , 2008 . 47 ( 5 ) , 612 -623 ; Ibrahim et al. , 2007. Diabetes 60 ( 4 ) , 1122 Optometry 79( 3 ), 133 - 137) and corticosteroids. 1133; Krady et al. , 2005 . Diabetes 54 (5 ) , 1559 - 1565; Vin [0006 ] Keeping the free margin of the eyelid clean is cent et al. , 2007 . Diabetes 56 ( 1 ) :224 - 230 ). fundamental for eliminating growing pathogens . Oral tetra [0013 ] Tetracycline and its derivatives have been proven cyclines are a fundamental complementary treatment to ease to have an anti - inflammatory effect and neuroprotective the symptoms of blepharitis (Dougherty et al. , 1991. Invest. effects , in addition to anti -bacterial effects , in cultures and in Ophthalmol . Vis . Sci. 132 ( 11 ) , 2970 - 2975 ) . Oral tetracy animal models. With respect to DR , some studies have clines are also used in certain apical corneal barrier disrup proven that doxycycline at low doses inhibits microglia tions (De Paiva et al. , 2006 . Invest. Ophthalmol. Vis . Sci . inflammatory changes, metalloproteinase activity and cell 47 ( 7 ) , 2847 - 56 ) and in other pathologies of the anterior pole apoptosis (Wang et al. , 2005. Neurochem Int. 47 ( 1- 2 ), 152 (Pinna et al. , 1999 . Br. J . Ophthalmol. 83 ( 7 ), 771 -773 ) . 158 ; Federici, 2011. Pharmacol. Res. 64 (6 ) , 614 -623 ; Bap Doxycycline is an antibiotic belonging to the tetracycline tiste et al ., 2005 . Neuroscience 134 ( 2 ) , 575 - 582 ; Griffin et family which is not usually used topically . De Paiva et al. al. , 2011. Pharmacol. Res. 63 (2 ) , 102 - 107 ) . US 2017 /0239307 A1 Aug . 24 , 2017

[0014 ] In a clinical trial including 5 patients with foveal [0029 ] In another preferred embodiment, the liposomes involvement due to diabetic macular edema who were are composed of lecithin with 50 to 99 % of phosphatidyl treated with 100 mg oral minocycline 2 times a day for 6 choline , more preferably with 70 to 95 % of phosphatidyl months, visual acuity of said patients improved and macular choline , and even more preferably with about 90 % of thickness dropped significantly compared with historic con phosphatidylcholine . trols from earlier studies (Cukras et al. , 2012 . Invest. Oph (0030 ). In another preferred embodiment, the liposomes thalmol. Vis. Sci. 53 ( 7 ) , 3865 - 3874 ) . are stabilized in an ionic solution , and more preferably in [0015 ] In summary, topical doxycycline may be minimally phosphate buffer. In another more preferred embodiment of invasive for the organism , lacking unwanted side effects this aspect of the invention , the pH of the phosphate buffer such as damage to the gastrointestinal tract , and its protec is adjusted to a value between 4 and 10 , more preferably tive effects on the microvasculature may delay the onset of between 5 and 9 , and even more preferably between 6 and DR . [ 0016 ]. Like other tetracyclines, doxycycline is an antibi [0031 ] In another preferred embodiment, the liposomes otic that has a stability problem . It loses microbial activity are stabilized in a non - ionic solution . More preferably , the as it is broken down and may even become toxic . non - ionic solution is selected from a mannitol solution and [0017 ] Liposomes could be a way to integrate doxycy a glucose solution , and it is more preferably a mannitol cline , which increases its stability . solution . Even more preferably , the mannitol solution has a concentration between 1 and 20 % , preferably between 2 . 5 BRIEF DESCRIPTION OF THE INVENTION and 10 % , and more preferably about 5 % mannitol. Even [ 0018 ] The author of the present invention has developed much more preferably, the pH of the solution is adjusted to and verified that a topical doxycycline composition could be a value between 3 and 9 , more preferably between 4 and 8 , useful for the treatment of blepharitis , disorders of the and even more preferably between 5 and 7 . anterior surface of the eye involving infection and /or inflam [0032 ] In another preferred embodiment, the liposomes mation . The topical route would prevent the side effects have a final size between 20 and 1000 nm , more preferably caused by oral administration . between 50 and 500 nm , even more preferably between 100 [0019 ] Other applications in addition to those already and 300 nm , and even much more preferably about 200 nm . described could be : [0033 ] In another preferred embodiment, the composition [0020 ] The prophylaxis of intraoperative infections has a doxycycline concentration between 0 .01 and 5 % , more such as endophthalmitis in blepharitis patients . preferably between 0 .025 and 1 % , even more preferably [0021 ] Dry eye , ocular rosacea . between 0 .04 and 0 .06 % , and even much more preferably [0022 ] Use in emergencies for traumas and ulcerations . about 0 .05 % . [0023 ] For the treatment, prevention and to avoid pro [0034 ] In another preferred embodiment, the composition gression of diabetic retinopathy. is a pharmaceutical composition . More preferably , the com [0024 ] Therefore, a first aspect of the invention relates to position further comprises a pharmaceutically acceptable the use of a composition , hereinafter composition of the vehicle . Even more preferably , the composition further invention , comprising doxycycline or any of its pharmaceu comprises another active ingredient . tically acceptable salts, esters , tautomers, solvates and [ 0035 ] In another preferred embodiment, the liposomes hydrates , or any combinations thereof, in the production of comprise antioxidants . More preferably , they further com a medicament for the prevention , improvement and /or treat prise antioxidants . ment of ocular pathologies . Alternatively, it relates to a 0036 ] In another preferred embodiment of this aspect of composition comprising doxycycline or any of its pharma the invention , the composition is sterilized . ceutically acceptable salts , esters , tautomers, solvates and [0037 ] A second aspect of the invention relates to a dosage hydrates , or any combinations thereof, for use in the pre form , hereinafter dosage form of the invention , comprising vention , improvement and / or treatment of ocular patholo the composition of the invention . gies . [0038 ] In a preferred embodiment of this aspect, the [0025 ] In a preferred embodiment of this aspect of the dosage form of the invention is selected from the list invention , the composition is a composition for topical consisting of: dressing , ointment, paste , cream , solution , administration . In another preferred embodiment, the ocular suspension , emulsion , lotion , liniment, jelly , gel , foam , pathology is selected from : blepharitis , microthrombosis in powder, or any combinations thereof . More preferably , it is the anterior pole and chorioretinal vascular disorders , or any a solution , and even more preferably an ophthalmic solution . combinations thereof. [0039 ] A third aspect of the invention relates to the use of [0026 ] In another preferred embodiment of the invention , the dosage form of the invention in the production of a the ocular pathology is diabetic retinopathy. medicament for the prevention , improvement and /or treat [0027 ] In another preferred embodiment, the doxycycline ment of ocular pathologies . Alternatively , it relates to the is included in liposomes . More preferably , the liposomes dosage form of the invention for use in the prevention , have a cationic character , and even more preferably , a improvement and /or treatment of ocular pathologies . neutral character. [0040 ] In a preferred embodiment of this aspect of the 10028 ] In another preferred embodiment, the composition invention , the composition is a composition for topical of the invention has a concentration between 0 . 5 and 50 % of administration . In another preferred embodiment, the ocular liposomes , more preferably between 1 and 25 % , more pathology is selected from : blepharitis , microthrombosis in preferably between 2 and 10 % , even more preferably the anterior pole and chorioretinal vascular disorders , or any between 4 and 6 % , and even much more preferably 5 % of combinations thereof. In another preferred embodiment of liposomes . the invention , the ocular pathology is diabetic retinopathy. US 2017 /0239307 A1 Aug . 24 , 2017

DESCRIPTION OF THE DRAWINGS [0049 ] The IUPAC nomenclature is (22 ,48 ,4aR , 55 ,5aR , [0041 ] FIG . 1 . Ocular dryness test record obtained by 6R , 12aS ) - 2 - amino -hydroxymethylidene ) - 4 -dimethyl means of Schirmer 's test in which it can be seen that after amino - 5 , 10 , 11, 12a - tetrahydroxy -6 -methyl - 4a , 5 ,5a ,6 -tetra treatment , moisture in the eye increased as a result of this hydro - 4H - tetracene - 1 , 3 , 12 - trione and the CAS number is treatment . 564 - 25 - 0 . [0042 ] FIG . 2 . Individual analysis of each patient accord [ 0050 ] The compounds of the present invention repre ing to dry eye questionnaire score . All patients completed a sented by formula ( 1 ) can include isomers , depending on the questionnaire to evaluate the symptoms derived from presence of multiple bonds, including optical isomers or blepharitis - dry eye like disease . In all the cases , symptoms enantiomers , depending on the presence of chiral centers . improved after treatment with doxycycline with a significant Individual isomers , enantiomers or diastereoisomers and drop in said score . mixtures thereof fall within the scope of the present inven 10043 ] FIG . 3 . Overall results with the sum of all the tion , i . e . , the term isomer also refers to any mixture of scores in all patients in the dry eye questionnaire . Symptoms isomers , such as diastereomeric isomers , racemic isomers , decreased significantly after treatment with doxycycline . etc . , even the optically active isomers thereof or mixtures This figure complements FIG . 2 . thereof in different proportions. Individual enantiomers or [0044 ] FIG . 4 . Record of the patient' s degrees of hyper diastereoisomers, as well as mixtures thereof , can be sepa emia (red eye , redness of the eye ) before and after treatment rated by means of conventional techniques . with topical doxycycline according to the Oxford scale . In [0051 ] Likewise , the scope of this invention includes the all cases , this hyperemia was considerably less after this prodrugs of the compounds of formula ( I ) . As it is used treatment. herein , the term “ prodrug” includes any derivative of a DETAILED DESCRIPTION OF THE compound of formula ( I ) , for example and in a non - limiting INVENTION manner : esters ( including carboxylic acids esters , amino [ 0045 ] The authors of the present invention have devel acid esters , phosphate esters , sulfonate esters of metal salts , oped a doxycycline composition in liposomes with anti etc . ) , carbamates , amides , etc . , which , when administered to infection and anti- inflammatory effects for topical use . an individual, can be transformed directly or indirectly into [ 0046 ] Therefore , a first aspect of the present invention said compound of formula ( I ) in the mentioned individual. relates to the use of a composition comprising doxycycline Advantageously , said derivative is a compound that or any of its pharmaceutically acceptable salts , esters , tau increases the bioavailability of the compound of formula ( I ) tomers , polymorphs , analogs , solvates and hydrates , or any when administered to an individual or enhances the release combinations thereof , in the production of a medicament for of the compound of formula ( 1 ) in a biological compartment . the prevention , improvement and /or treatment of ocular The nature of said derivative is not critical provided that it pathologies. Alternatively , it relates to a composition com can be administered to an individual and it provides the prising doxycycline or any of its pharmaceutically accept compound of formula (I ) in a biological compartment of an able salts , esters , tautomers , polymorphs , analogs , solvates individual. Said prodrug can be prepared by means of and hydrates, or any combinations thereof, for use in the conventional methods known by those skilled in the art . prevention , improvement and / or treatment of ocular [0052 ] As it is used herein , the term " derivative” includes pathologies . both pharmaceutically acceptable compounds, i . e . , deriva [0047 ] Preferably , the administration of the composition tives of the compound of formula ( I ) which can be used in of the invention is by topical route . the production of a medicament or food compositions , and [0048 ] In this specification , doxycycline is understood as non - pharmaceutically acceptable derivatives since they may an antibiotic from the tetracycline group having the chemi be useful in the preparation of pharmaceutically acceptable cal formula C22H24N20g. It is a semi- synthetic tetracycline derivatives . related derivative . It has a broad - spectrum bacteriostatic 100531. The compounds of the invention can be in crystal effect and acts by inhibiting protein synthesis , blocking the line form as free compounds or solvates . In this sense , as it binding of transfer RNA to the ribosomal complex . Specifi is used herein the term “ solvate ” includes both pharmaceu cally , binding occurs in the 30S ribosomal subunit of sen tically acceptable solvates, i . e ., solvates of the compound of sitive organisms. Furthermore , it has anti - inflammatory formula ( I ) which can be used in the production of a action , acting on polynuclear neutrophils involved in the medicament, and non -pharmaceutically acceptable solvates inflammatory stage of specific infections. This antibiotic which may be useful in the preparation of pharmaceutically prevents growth and propagation of both Gram positive and acceptable solvates or salts . The nature of the pharmaceu Gram negative bacteria . It has the following formula ( I ) : tically acceptable solvate is not critical provided that it is pharmaceutically acceptable . In a particular embodiment, the solvate is a hydrate . The solvates can be obtained by Formula ( 1) conventional solvation methods known by those skilled in OH 0 0 OH OH the art . [0054 ] For application in therapy , the compounds of for mula ( 1 ) , its salts , prodrugs or solvates, will preferably be in H?N a pharmaceutically acceptable or substantially pure form , i . e . , having a pharmaceutically acceptable level of purity excluding normal pharmaceutical additives such as diluents . Hull. and carriers , and not including material considered toxic at Z normal dosage levels . The levels of purity for the active ingredient are preferably greater than 50 % , more preferably greater than 70 % , and even more preferably greater than US 2017 /0239307 A1 Aug . 24 , 2017

90 % . In a preferred embodiment, they are greater than 95 % lipids are added to increase their stability . Liposome size of the compound of formula ( I ) or of its salts, solvates or usually ranges between 20 nm and 500 um and liposomes prodrugs . can be classified by size : liposomes ranging from 20 to 70 [0055 ] In another preferred embodiment , the ocular nm are referred to as Small Unilamellar Vesicles (SUVs ) , pathology is selected from : blepharitis , microthrombosis in liposomes ranging from 70 to 400 nm are referred to as the anterior pole and chorioretinal vascular disorders , or any Large Unilamellar Vesicles (LUVs ) . It is also possible to combinations thereof. In another preferred embodiment of form a special type of liposomes referred to as Giant the invention , the ocular pathology is diabetic retinopathy . Unilamellar Vesicles (GUVs ) having a size far larger than [ 0056 ] In this specification , blepharitis is understood to be the foregoing and a diameter ranging between about 10 and inflammation of the tissue forming the eyelid . It usually 100 um . On the other hand , there are also Oligolamellar originates from an irregular working of the glands in the Vesicles (OLVs ) which have a few superimposed layers , and eyelid margin that leads to irritation and scab formation , Multilamellar Vesicles (MLVS ) which have many superim which provides optimal conditions for the growth of bacteria posed layers . These liposomes have highly variable size that further irritate the eyelid and aggravate the process . If distributions and they can range from about 500 nm to 2000 the process is not stopped , progressive worsening will occur nm in the same sample . with painful inflammation of the eyelid margin , extreme 0064 ] In a preferred embodiment of this aspect of the discomfort on the ocular surface and even decreased vision . invention , the liposomes have a cationic character . In Blepharitis can be of two types: another preferred embodiment of this aspect of the inven [0057 ] Squamous blepharitis : patients present scaly tion , the cationic character is achieved by producing lipo eyelids due to its appearance and it is characterized by somes with physiological saline . the formation of scales between eyelashes that often [ 0065 ] In the present specification , physiological saline or fall into the eyes , causing the feeling of there being physiological saline solution is understood as an aqueous something in the eyes . The eyes are red . The margins of solution compatible with living organisms as a result of its the eyelids are red most of the time, giving the impres defined osmotic , pH and ionic strength characteristics . It sion that the patient has been crying, and it can cause usually consists of water , electrolytes, and additionally other local itching. It is the cause of local bacterial and fungal substances such as glucose . Its biochemical composition is infection on seborrheic skin . 0 . 9 % NaCl. [0058 ] Allergic blepharitis : It is a form of manifestation of a contact allergy , mostly to cosmetic products, for [0066 ] In another preferred embodiment of this aspect of example eyeshadows, eye pencils and blushes , as well the invention , the liposomes have a neutral character. In as cosmetic solvents for removing said products . How another preferred embodiment of this aspect of the inven ever, actually, any substance which contaminates the tion , the neutral character is achieved by producing lipo fingers and is brought to the eyes by means of the hands somes with purified water . can cause acute or chronic dermatitis of the eyelids, 0067] In the present specification , purified water is under such as and their saps, vegetables, acrylic plas stood as water improved or enriched in a laboratory with an tics or even medicaments for the legs or feet , to agent. Purified water is water treated for a specific use in mention a few examples . science or engineering. Three types of purified water can be [0059 ] In this specification , microthrombosis of the ante distinguished : distilled , double -distilled and deionized . rior pole is understood as the formation of thrombi in [0068 ] In a preferred embodiment of this aspect of the capillaries and vessels of small caliber located in the anterior invention , the composition has a concentration between 0 .5 part of the eyeball : conjunctiva , cornea and lens . and 50 % of liposomes ,more preferably between 1 and 25 % , [0060 ] In this specification , chorioretinal vascular disorder more preferably between 2 and 10 % , more preferably is understood as that situation in which blood does not between 4 and 6 % , and even more preferably about 5 % . circulate the way it should due to any possible event in the [0069 ] In a preferred embodiment of this aspect of the chorioretinal area . invention , the liposomes are composed of lecithin with [0061 ] In this specification , diabetic retinopathy is under 50 - 99 % of phosphatidylcholine , more preferably with stood as an ocular diabetes complication which is caused by 70 - 95 % of phosphatidylcholine , and even more preferably the deterioration of blood vessels irrigating the retina . Dam with about 90 % of phosphatidylcholine . age to retinal blood vessels can result in the blood vessels [0070 ] Phosphatidylcholine is a phospholipid and usually experiencing a leakage of fluid or blood . If the disease the major component of lipid bilayers . Phospholipid is made progresses, new blood vessels form and the fibrous tissue up of a choline head group and glycerophosphoric acid , with proliferates in the retina , which results in deteriorating a variety of fatty acids, one of them being a saturated fatty vision since the image sent to the brain becomes blurred . acid and one of them an unsaturated fatty acid . Phospholi [0062 ] In a preferred embodiment of this aspect of the pase D catalyzes phosphatidylcholine hydrolysis to form invention , the doxycycline is included in liposomes. phosphatidic acid , releasing the cytosol- soluble choline head [ 0063] In this specification , liposomes are understood to group . However, phosphatidylcholine is a neutral lipid with be spherical vesicles with a phospholipid membrane . The an electric dipole moment of ~ 10 D . arrangement of phospholipids in liposome formation causes [0071 ] In a preferred embodiment of this aspect of the both the inside and outside to be water - soluble , whereas the invention , the liposomes are stabilized in an ionic solution , inside is fat- soluble . Use thereof as transporters for trans preferably phosphate buffer . In another preferred embodi porting substances between the exterior and the interior of a ment of this aspect of the invention , the pH of the phosphate cell has been described , hence the interest thereof in bio buffer is adjusted between 4 and 10 , more preferably technology . Liposomes are usually produced from lecithin between 5 and 9 , and even more preferably between 6 and obtained from soy, egg yolk and brain tissue, although other 8 . US 2017 /0239307 A1 Aug . 24 , 2017

[0072 ] In a preferred embodiment of this aspect of the istration in solid form . The compositions can be combined invention , the liposomes are stabilized in a non - ionic solu with several inert vehicles or excipients , including but not tion . In a preferred embodiment of this aspect of the inven limited to agglutinants such as microcrystalline cellulose , tion , the non - ionic solution is preferably selected from a tragacanth gum , or gelatin ; excipients such as starch or mannitol solution and a glucose solution , preferably a man lactose ; dispersing agents such as alginic acid or corn starch ; nitol solution . In a preferred embodiment of this aspect of lubricants such as magnesium stearate , glidants such as the invention , the mannitol solution is 1- 20 % , preferably colloidal silicon dioxide ; sweetening agents such as sucrose 2 . 5 - 10 % , and more preferably about 5 % . In another pre or saccharin ; or aromatizing agents such as mint or methyl ferred embodiment of this aspect of the invention , the pH of salicylate . the mannitol solution is adjusted between 3 and 9 , more [0083 ] A second aspect of the invention relates to a dosage preferably between 4 and 8 , and even more preferably form , hereinafter dosage form of the invention , comprising between 5 and 7 . the composition according to the first aspect of the inven 10073 ] In a preferred embodiment of this aspect of the tion . invention , the liposomes have a final size between 20 and [0084 ] In this specification , “ dosage form ” is understood 1000 nm , more preferably between 50 and 500 nm , even as the mixture of one or more active ingredients with or more preferably between 100 and 300 nm , and even more without additives having physical characteristics for suitable preferably about 200 nm . dosing , conservation , administration and bioavailability . [0074 ] In a preferred embodiment of this aspect of the 100851 In a preferred embodiment of this aspect of the invention , the liposomes have a doxycycline concentration invention , the dosage form is selected from the list com between 0 .01 and 5 % , more preferably between 0 .025 and prising : dressing , ointment , paste , cream , solution , suspen 1 % , more preferably 0 . 04 - 0 . 06 % , and even more preferably sion , emulsion , lotion , liniment, jelly , gel , foam , powder, or about 0 .05 % . any combinations thereof. [0075 ] In a preferred embodiment of this aspect of the [0086 ] A " dressing ” or “ patch ” is a dosage form consisting invention , the composition is a pharmaceutical composition . of a solid or semisolid form containing the active ingredient [0076 ] In a preferred embodiment of this aspect of the or ingredients and additives , spread on a piece of fabric , invention , the composition further comprises a pharmaceu plastic or adhesive tape , acting as a support and protection , tically acceptable vehicle . in addition to having an occlusive effect and macerating [0077 ] In a preferred embodiment of this aspect of the action which in addition allows it to come into direct contact invention , the composition further comprises another active with skin and to soften with body temperature . ingredient. [0087 ] An “ unguent” or “ ointment” is a dosage form [0078 ] As it is used herein , the term “ active ingredient” , consisting of a preparation having a soft consistency con " active substance ” , “ pharmaceutically active substance ” , or taining the active ingredient or ingredients and additives " pharmaceutically active ingredient ” means any component incorporated in a suitable base giving it body and consis that may provide a pharmacological activity or another tency . It is adhered and applied to the skin and mucous different effect in the diagnosis , cure , mitigation , treatment , membranes . This base can be fat - or water -soluble , generally or prevention of a disease, or that affects the body structure anhydrous or with a maximum of 20 % water. It is also or function of humans or other animals . The term includes referred to as hydrophilic unguent when it contains a base those components that promote a chemical change in the that can be washed away or removed with water. production of the drug and are present in the drug in an [0088 ] “ paste ” is a dosage form consisting of a semi envisaged modified form , providing the specific activity or solid form containing the active ingredient or ingredients effect. and additives , made based on a high concentration of [ 0079 ]. In a preferred embodiment of this aspect of the insoluble powders (20 to 50 % ), in weak abrasive or absor invention , the liposomes contain antioxidants . bent fatty or aqueous bases combined with soaps . [0080 ] In a preferred embodiment of this aspect of the [0089 ] A " cream ” is a dosage form consisting of a liquid invention , the liposomes contain stabilizers . or semisolid preparation containing the active ingredient or 0081] In a preferred embodiment of this aspect of the ingredients and additives required for obtaining an emul invention , the composition is sterilized . The sterilization sion , generally an oil - in -water emulsion , with a water con process for sterilizing the composition can be carried out by tent greater than 20 % . any sterilization method known in the state of the art . In a [ 0090 ] A “ solution ” is a dosage form consisting of a preferred embodiment of this aspect of the invention , ster transparent and homogenous liquid preparation obtained by ilization is achieved by filtration . dissolving the active ingredient or ingredients and additives [0082 ] The compositions of the present invention can be in water and is intended for external or internal use . In the formulated for administration to an animal, and more pref case of injectable solutions for the eyes and ears , they must erably to a mammal, including humans, in a variety of forms be sterile . The term “ solution ” includes solutions. known in the state of the art . In this sense , the compositions [0091 ] A “ suspension ” is a dosage form consisting of a can be , without limitation , in a sterile aqueous solution or in dispersed system formed by two phases which contain the biological fluids , such as serum . The aqueous solutions may active ingredient or ingredients and additives . One of the or may not be buffered and they have additional active or phases , the continuous or external phase , is generally a inactive components . The additional components include liquid or a semisolid , and the dispersed or internal phase is salts for modulating ionic strength , preservatives and other made up of solids ( active ingredients ) that are insoluble but substances including , but not limited to , antimicrobial dispersible in the external phase . In the case of injectable agents , antioxidants , chelating agents , and the like , and suspensions, they must be sterile . nutrients including glucose , dextrose , vitamins and minerals . [0092 ] An " emulsion ” is a dosage form consisting of a Alternatively , the compositions can be prepared for admin heterogeneous system generally made up of two liquids not US 2017 /0239307 A1 Aug . 24 , 2017 miscible with one another, in which the dispersed phase is description and in part from putting the invention into formed by small globules distributed in the vehicle in which practice . The following examples and drawings are provided they are immiscible . The dispersed phase is also known as by way of illustration and do not seek to limit the present an internal phase and the dispersion medium is known as an invention . external or continuous phase . There are water- in -oil - type or oil - in -water - type emulsions and they can be presented as Examples of the Invention semisolids or liquids . The active ingredient or ingredients and additives can be in the external or internal phase . Example 1 : Experimental Study with Eye Drops [0093 ] A “ lotion ” is a dosage form that can be presented Containing 0 .05 % Doxycycline in Blepharitis as a solution , suspension or emulsion , containing the active ingredient or ingredients and additives , and the dispersing Material and Methods agent of which is predominantly water. [ 0094 ) A “ liniment” is a dosage form consisting of an [0104 ] The authors of the present invention proposed to emulsion , solution or liquid presentation containing the first evaluate experience with the use of doxycycline in active ingredient or ingredients and additives the vehicle of blepharitis before designing a clinical trial. The evaluation which is an aqueous , alcoholic or oily vehicle . included 12 patients with this disease whose Cornea and [ 0095 ] A " jelly ” is a dosage form consisting of a semisolid Contact Lens Research Lab hyperemia score was maximum colloid containing the active ingredient or ingredients and ( 4 ) and in whom signs of staphylococcal infection were additives , the water -soluble base of which is generally made present ( collarettes and telangiectasias ) and the disease was up of gums such as tragacanth gum , other bases used are : confirmed due to this bacterium . glycerin , pectin , alginates, boroglycerine compounds , syn thetic derivatives or natural substances such as carboxym Results ethyl cellulose . [ 0096 ] A " gel ” is a dosage form consisting of semisolid Conjunctival Culture preparation containing the active ingredient or ingredients [0105 ] The twelve patients showed a positive staphylo and additives, solids in a liquid which can be water, alcohol coccus culture before treatment with doxycycline . After or oil , such that a network of particles trapped in the liquid treatment with these 0 .05 % eye drops for three weeks , said phase is formed . culture was repeated ; none of the twelve patients showed a [ 0097 ] A " foam ” is a dosage form consisting of a semi positive staphylococcus culture at that time. solid preparation formed by two phases: a liquid phase carrying the active ingredient or ingredients and additives , Schirmer ' s Test and another gaseous phase carrying propellant gas for the product to come out in the form of a cloud . [0106 ] This test is used to assess dry eye status in blephari [0098 ] " Powder” is a dosage form consisting of a solid tis (in millimeters) . As can be confirmed — though even in form containing the active ingredient or ingredients and the absence of validated statistical tests , all patients showed additives that are finely grounded and mixed to assure a baseline tear secretion lower than that shown after treat homogeneity . ment. This leads the authors to think of the possibility of [0099 ] In a preferred embodiment of this aspect of the using doxycycline against this dry syndrome (FIG . 1 ) . invention , the dosage form is a solution , preferably an ophthalmic solution or eye drops . Symptom Score According to the Dry Eye Questionnaire [ 0100 ) A third aspect of the invention relates to the use of [0107 ] This test was designed (see test design literature ) the dosage form of the invention in the production of a for assessing the symptoms the patient experiences and they medicament for the prevention , improvement and / or treat can be expressed by means of a score based on questions ment of ocular pathologies. Alternatively , the invention about these symptoms. It can be seen how each and every relates to the dosage form of the invention for use in the one of the patients has a higher score before treatment, prevention , improvement and / or treatment of ocular which indicates that all the patients of the sample had at least pathologies . moderate symptoms, most of them being severe . After [0101 ] In a preferred embodiment of this aspect of the applying eye drops containing 0 .05 % doxycycline , these invention , the composition is a composition for topical symptoms decrease in all cases to mild (FIG . 2 ). administration . In another preferred embodiment, the ocular [0108 ] FIG . 3 summarizes all the scores before and after pathology is selected from : blepharitis, microthrombosis in treatment. A total score reduction can also be seen with the anterior pole and chorioretinal vascular disorders , or any respect to symptoms. combinations thereof. 0102 ] As it is used herein , the term " medicament ” refers to any substance used for the prevention , diagnosis , relief, Hyperemia According to the Cornea and Contact Lens treatment or cure of diseases in humans and animals . In the Research Lab Scale context of the present invention , the disease is an ocular [0109 ] This scale allows including patients in this study disease , preferably blepharitis , microthrombosis in the ante based on hyperemia ( redness of the eye ) caused by this rior pole and / or chorioretinal vascular disorders . staphylococcal infection . The range thereof fluctuates [0103 ] Throughout the description and claims the word according to the severity of hyperemia , between Grade I and " comprises” and variants thereof do not seek to exclude Grade IV . As can be seen in the following graph , almost all other technical features , additions , components or steps . For the patients had severe grades of hyperemia before treat those skilled in the art, other objects , advantages and fea ment. All the patients subsequently returned to minimum tures of the invention will be inferred in part from the hyperemia levels ( FIG . 4 ) . US 2017 /0239307 A1 Aug . 24 , 2017

[0110 ] In addition to these parameters , others such as the tobramycin and dexamethasone in the form of eye drops was safety of the drug and its side effects were evaluated . In no started , reinforcing improvement of his symptoms with case were there any withdrawals from treatment, epithelial (topical anti -histamine ) Zaditen eye drops . keratitis or toxicities in the anterior pole of the eye resulting [0119 ] No diabetes- induced retinal lesions at that time. from this treatment, nor were there any significant increases [0120 ] Visit to the clinic on 11 Feb . 2009 : In this visit to in intraocular pressure . the clinic and due to the patient' s symptoms worsening [ 0111] The negative results obtained in all the staphylo again with seborrheic , squamous blepharitis and new epi coccus cultures after treatment, the absence of side effects sodes of styes, a decision was made to apply a specific and the improvement of patients ' symptoms led the authors treatment with high doses of oral doxycycline for 20 days of the invention to think of the long -term effectiveness that plus topical treatment with eye drops containing diclofenac this drug may have in blepharitis , since this disease has no and tobramycin with dexamethasone . specific treatment at present. The results thereof are very [0121 ] No diabetes -induced retinal lesions at that time. promising and have prompted the authors of the invention to [0122 ] Visit to the clinic on 12 May 2009: The patient conduct a prospective clinical trial with a larger sample size . again visited the clinic with worsening symptoms and men tioned that he did not take the complete treatment due to Example 2 : Patient with Blepharitis and Glycemic intolerance to oral doxycycline . Hementioned an episode of Decompensation gastritis as a result of oral doxycycline and he therefore [0112 ] A 72 -year old male patient treated in the clinic for abandoned the treatment. Since doxycycline is particularly redness of the eye which he has been suffering for years . He indicated for this pathology , a decision was then made to received treatment provided by his primary care physician in prescribe an individualized formula of eye drops containing the clinic but has not noticed any improvement , so he has 0 .05 % doxycycline with dexamethasone , and a topical treat requested specialized ophthalmology assistance . As a point ment guideline for eye drops with dexamethasone and of background interest, the patient suffers diabetes with poor 0 .05 % doxycycline solution was indicated . glycemic control. Supervision of the fundus of the eye was [0123 ] No diabetes - induced retinal lesions at that time. performed in all check - ups due to diabetes. 0124 ] Visit to the clinic on 15 Jun . 2009 : The patient [0113 ] First visit to the clinic on 5 Mar . 2008 : Upon visited the clinic to review this treatment , mentioning liter examination of both eyes , signs of chronic anterior and ally that “ he is much better” ( as reflected in the patient' s posterior blepharitis , redness of the eye , telangiectasias , history ) . The absence of telangiectasias , collarettes and collarettes , secretions and mild -moderate levelkeratitis were inflammation as well as less redness were confirmed during confirmed . Treatment with tobramycin and dexamethasone examination . At that time and seeing the good result of in the form of eye drops and artificial tears was established therapy with eye drops containing 0 .05 % doxycycline with at that time. dexamethasone , treatment was prescribed and prescriptions [0114 ] In this period of time and as a result of the for an additional 40 days were given due to the chronic blepharitis he suffered , infectious granules ( styes ) appeared nature of the process . In these future preparations, dexam on his eye lids and they had to be surgically removed ethasone was excluded from the formulated product since it ( chalazion ) . The condition was then classified as severe can cause glaucoma when topically applied in the form of blepharitis with a poor response to standard treatment . eye drops for more than 25 days , so it was excluded and the [0115 ] As information of interest, the patient ' s blood patient was left with a topical preparation of 0 .05 % doxy glucose levels for the years 2007 and 2008 are provided cycline eye drops. below : 10125 ] No diabetes - induced retinal lesions at that time. [0126 ] Visit to the clinic on 9 Feb . 2010 : After the previ TABLE 1 ous cycle of topical doxycycline treatment, the patient remained asymptomatic although a new episode of sebor Blood glucose level of the patient for the years 2007- 2008 rheic blepharitis appeared after withdrawing doxycycline when the prescriptions finished . A new treatment was pre Date scribed with topical doxycycline until the new check -up in 1 Feb . 20 Feb . 29 Mar. 19 Jul. 18 Sep . November and prescriptions were given . 2007 2008 2008 2008 2008 [0127 ] No diabetes -induced retinal lesions at that time. Blood glucose 172172 159 141 150150 153 0128 ]. Visit to the clinic on 8 Nov . 2010 : The patient (mg / dl ) mentioned that he has continued with treatment because the symptoms of blepharitis reappeared when he abandoned [ 0116 ] It must be borne in mind that for a fasting blood treatment for a period of a few weeks, which irritates him ; glucose test , a level between 70 and 100 milligrams per therefore he has continued with doxycycline eye drops deciliter (mg /dl ) is considered normal . For a random blood indefinitely . The patient himself requested doxycycline eye glucose test , a normal result will depend on the last time the drops in the pharmacy . patient ate .Most of the time, the blood glucose level will be [0129 ] No diabetes - induced retinal lesions at that time. below 125 mg /dl . This patient often showed figures up to [0130 ] Visit to the clinic on 1 Aug . 2011: The patient twice what is considered normal in a diabetic process . visited the clinic for diabetes and blepharitis check - ups. He [0117 ] No diabetes- induced retinal lesions at that time. mentioned that he has been using doxycycline eye drops [0118 ] Visit to the clinic on 21 Nov. 2008 : The patient whenever the need arises depending on symptoms, but he mentioned that he had not noticed any significant improve was administrating the eye drops almost continuously ment with the previous treatment, nor even had any wors because if he stops using it, discomfort and red eye come ening after withdrawing treatment. A new treatment with back . US 2017 /0239307 A1 Aug . 24 , 2017

[0131 ] No diabetes - induced retinal lesions at that time. use of plants from the genera Matricaria , Thymus and [0132 ] As information of interest, the patient ' s blood in the production of a medicament for the relief, improve glucose levels for the years 2010 , 2011 and 2012 are ment, prevention and / or treatment of ocular pathologies, and provided below : more preferably for the treatment of dry eye syndrome. TABLE 2 Background of the Invention 2 Blood glucose level of the patient for the years 2010 - 2012 [ 0143 ] Dry eye syndrome is an extremely common disease affecting millions of people . Its prevalence according to the Date environment can reach up to 35 % , even reaching up to 75 % 14 14 18 20 9 22 18 in daily visits to clinics in Spain . The incidence tends to May Nov. Nov. Dec . Sep . Sep . Sep . increase due to lifestyle changes, pollution , life expectancy , 2010 2010 2010 2010 2011 2011 2012 the use of screens, eye surgery and the use of contact lenses . It has a multifactorial origin and its symptoms include eye Blood glucose 146 232 170 175 201 219 147 discomfort , reduced visual acuity and changes in relation to (mg / dl) tears either due to deficiency or evaporation thereof, in addition to a greater susceptibility to infections . Dry eye is [0133 ] There were no signs of diabetic retinopathy during accompanied by an increased tear osmolarity and ocular the entire time this patient underwent doxycycline treatment surface inflammation . Various treatments have been pro both orally and in the form of eye drops, i . e . , from 11 Feb . posed and they range from simple lubrication to the use of 2009 to present. surgical or immunosuppressive means. According to the [0134 ] In 2013 and given the improvement of his symp experience of the authors of the present invention , lubricants toms, he began to stop using eye drops containing doxycy as a first line treatment are rather ineffective and do not bring cline and to control his blood glucose levels . about any anti- inflammatory , anti - infection or epithelization [0135 ] Today, he shows no retinal alterations as a result of effect that the ingredients to be evaluated in the formula of diabetes and his blood glucose levels are normal. the present invention do have . [0136 ] Based on the foregoing it can be concluded that the 10144 ] From the clinical viewpoint, dry eye diseases diabetes of the diabetic patient with high blood glucose included in the tear film dysfunction syndrome have various levels and poor endocrine -metabolic control did not progress etiological causes , different combinations of anatomical and into diabetic retinopathy . pathological involvements and several degrees of severity . A [0137 ] Likewise , based on the results obtained in the dacryology specialist must know these three parameters , administration of doxycycline to this patient, the authors of quantify them and accordingly establish the appropriate the invention think that there is a cause and effect relation treatment. Several classifications have been elaborated to ship between the administration of doxycycline and the that end . First , an etiological classification into age - related , absence of the onset of diabetic retinopathy despite the hormonal, pharmacological, immunopathic , hyponutri patient having a high blood glucose level for years , besides tional, dysgenetic , inflammatory , traumatic , neurodepriva the curing of his blepharitis which remains inactive at tive and tantalic causes , each of these groups including present. several variants . Second , a histopathological classification or ALMEN , an acronym for aquodeficiency , lipodeficiency , Example 3 : Composition of the Eye Drops mucodeficiency, epitheliopathy and the involvementof other Containing Doxycycline in Liposomes non -ocular exocrine glands. Third , a classification of sever ity into five grades : subclinical ( symptoms in situations of [ 0138 ] The eye drops used contain doxycycline in lipo overexposure ) , mild ( common symptoms) , moderate ( re somes . These liposomes have been produced by means of versible symptoms and signs ), severe (irreversible symp the sonication method with subsequent extrusion . The lipo toms and signs) and disabling ( irreversible loss of sight due somes have a final diameter of 200 nm . Fundamentally, the to corneal damage ). composition of these liposomes is based on soy lecithin with [0145 ] Dry eye syndrome can also be caused by Sjögren 's 90 % phosphatidylcholine , and the liposomes are produced syndrome. Sjögren ' s syndrome is an autoimmune disorder with purified water or physiological saline , and they will in which tear- producing cells are destroyed . The main have a neutral or positive character , respectively , depending symptoms of Sjögren ' s syndrome are dryness , burning and on this production . The final phospholipid concentration in the feeling of there being a foreign body in the eye , being the eye drops is therefore 5 % . able to lead to blindness . [0139 ] Doxycycline is at a concentration of 0 .05 % within [0146 ] A wide range of treatments , i .e . , lubricating eye the liposome. drops ranging from common topical anti- inflammatory eye [0140 ] The use of antioxidants and/ or stabilizer has been drops such as diclofenac , corticoids such as dexamethasone , contemplated . Furthermore , it has been sterilized means of to immunomodulators and immunosuppressants such as a filtration method using 0 . 22 um filters. cyclosporin and tacrolimus , have been used for this pathol ogy . All these drugs have side effects, are not effective for all Invention 2 cases and require preservatives in their solution , which do [0141 ] Composition for the Relief, Improvement, Preven not help to provide stability to the ocular surface , requiring tion and / or Treatment of Dry Eye Syndrome to continuously monitor the patient to whom these drugs [0142 ] The present invention is comprised in the field of have been administered in order to check for the absence of biology and medicine , and relates to the use of several said side effects (Devecl and Kobak , 2014 . Int. Ophthalmol. in the production of a medicament for ophthalmol - January 19 ) . Lubricants such as carmellose and hyaluronate , ogy therapy . Preferably , the present invention relates to the without any anti- inflammatory, anti- infection or healing US 2017 /0239307 A1 Aug . 24 , 2017 capacity , are often used . Washes with home- made chamo [0161 ] In another preferred embodiment of this aspect of mile preparations that may be safer and more effective than the invention , the proportion of a ) is as follows: 1 - 48 % the simple use of lubricants are empirically known in Matricaria , 1 -48 % Thymus and 1 -48 % Aloe . More prefer ophthalmology . Combined with other active ingredients , an ably , the proportion of a ) is as follows: 3 . 3 - 20 % Matricaria , inexpensive effective product without chemical media and 2 . 3 - 11. 1 % Thymus and 4 . 4 -22 . 3 % Aloe , and even more preservatives that are damaging to the ocular surface , reduc preferably 7 . 5 % Matricaria , 5 % Thymus and 10 % Aloe . ing inflammation and red eye caused by this pathology with a multifactorial cause , could be developed . DESCRIPTION OF THE DRAWINGS [0162 ] FIG . 5 . ( A ) Hyperemia ( redness of the eye ) reduced Brief Description of the Invention 2 after treatment in a case of dry eye syndrome associated with [ 0147 ] A first aspect of the invention relates to a compo chronic treatment of antihypertensive eye drops with pros sition , hereinafter composition of the invention , comprising taglandins lasting for more than 10 years . Improvement was plantmaterial from plants of the genera Matricaria , Thymus assessed 10 days after treatment in a case as severe as the and Aloe , the extracts of said plants , or an active ingredient one at hand . Patient from a cohort of 10 patients , which is obtained from said plant material or the extracts . the object of Example 4 of the invention : Treatment with [ 0148 ] In a preferred embodiment of this aspect , the Aloe , Matricaria and Thymus eye drops in patients with dry composition of the invention further comprises a pharma eye of any cause excluding Sjögren ' s syndrome . ceutically acceptable vehicle . In another preferred embodi [0163 ] ( B ) Improvement of hyperemia 8 and 24 hours mentm of this aspect, the composition of the invention further after applying Aloe, Matricaria and Thymus eye drops in red comprises another active ingredient . In another more pre eye resulting from dry syndrome associated with mild , ferred embodiment , the composition of the invention is a blepharitic -type infection that went away without the admin pharmaceutical composition . istration of other anti- inflammatory eye drops or topical 10149 ) A second aspect of the invention relates to the antibiotics . Patient extracted from Example 4 of the inven composition of the invention for use as a medicament, or tion : Treatment in patients with involvements and patholo alternatively , to the use of the composition of the invention gies of another type not related to dry eye syndrome: in the production of a medicament . Blepharitis : 2 cases . [0150 ] A third aspect of the invention relates to the com [0164 ] FIG . 6 . OSDI (Ocular Surface Disease Index or position of the invention for use in the relief, improvement , ocular comfort test ) questionnaire score before and after prevention and /or treatment of the dry eye syndrome, or treatment ( 3 weeks ) . The higher the score , the larger the alternatively , to the use of the composition of the invention number and the greater the intensity of the symptoms in the production of a medicament for the relief , improve derived from dry eye syndrome will be. A score of 0 to 100 ment, prevention and / or treatment of the dry eye syndrome. is given . This figure summarizes the score of the OSDI test [ 0151] A fourth aspect of the invention relates to the performed on a cohort of 10 patients which is the object of composition of the invention for use in the relief, improve Example 4 . ment, prevention and treatment of Sjögren ' s syndrome, or alternatively , to the use of the composition of the invention in the production of a medicament for the treatment of Detailed Description of the Invention 2 Sjögren ' s syndrome. [ 0165 ] The authors of the present invention have devel [ 0152] A fifth aspect of the invention relates to a dosage oped a composition based on natural products with an form , hereinafter dosage form of the invention , comprising anti- inflammatory and an anti - infection effect, in a correct the pharmaceutical composition of the invention . proportion , which are safer and have fewer side effects than [0153 ] In a preferred embodiment of this aspect, the common topical anti- inflammatory drugs such as diclofenac dosage form of the invention is selected from the list or other immunomodulators and immunosuppressants, and comprising : dressing , ointment, paste , cream , solution , sus these natural products in turn are more effective than the pension , emulsion , lotion , liniment, jelly, gel, foam , powder, simple use of lubricants . or any combinations thereof. In another more preferred [0166 ] Therefore, a first aspect of the invention relates to embodiment of this aspect, the dosage form of the invention a composition , hereinafter composition of the invention , is a solution , and even more preferably an ocular solution . comprising plant material from plants of the genera Matri [ 0154 ] A sixth aspect of the invention relates to a method caria , Thymus and Aloe , the extracts of said plants , or an for producing a composition comprising the steps of: active ingredient obtained from said plant material or the [ 0155 ] a ) mixing the plant material from plants of the extracts . genera Matricaria , Thymus and Aloe , the extracts of said [0167 ] In this specification , “ plant material” is understood plants , or an active ingredient obtained from said plant as either the aerial or subterranean parts of plants or other material or the extracts ; plant materials such as saps, resins , fatty oils , essential oils [ 0156 ] b ) adjusting the pH . and any other substances of this nature , and combinations [0157 ] A preferred embodiment of this aspect of the thereof , in crude form or in the form of plant preparations . invention further comprises : [0168 ] “ Extracts ” are concentrated preparations having a [0158 ] c ) sterilizing the solution . liquid , solid or intermediate consistency , usually obtained [ 0159 ] In another preferred embodiment of this aspect of from a fresh , more preferably dried , plantmaterial . For some the invention , the mixing in a ) is performed in water or a preparations , the material to be extracted may require prior hydrate. treatment, such as enzyme inactivation , grinding or degreas [0160 ] In another preferred embodiment of this aspect of ing , for example . The extracts are prepared by maceration , the invention , the mixing in a ) is performed in an anhydrous percolation or by other suitable validated methods using base . ethanol or another solvent. After the extraction , unwanted US 2017 /0239307 A1 Aug . 24 , 2017 substances are eliminated , if required . Extraction methods Aloe hereroensis , Aloe hexapetala , Aloe humillis, Aloe iner are known by the person skilled in the art and are described , mis, Aloe integra , Aloe aff. Jacksonii, Aloe jucunda , Aloe for example but without limitation , in the Royal Spanish juvenna , Aloe kniphofioides , Aloe kouebokkeveldensis. Aloe Pharmacopeia or in the European Pharmacopeia . Extraction lavranosii, Aloe lineata , Aloe lineata var. Lineata , Aloe technologies include , among others, supercritical fluid lineata var. Muirii , Aloe littoralis, Aloe lutescens, Aloe extraction and other more conventional methods , such as maculate , , , Aloe steam extraction methods , solution ( solid - liquid or liquid microstigma, Aloe mitriformis , Aloe mitriformis subsp . Dis liquid ) extraction methods and centrifugation extraction tans, Aloe modesta , Aloe morijensis, Aloe munchii , Aloe methods . ngobitensis , Aloe niebuhriana , Aloe nubigena , Aloe nyerien [ 0169 ] In this specification , " plant" is understood as all the sis , , Aloe peckii , Aloe peglerae , Aloe pen organisms which can be classified in the kingdom Viridi dens , Aloe penduliflora , , Aloe perryi , Aloe plantae, including green and land plants ( Embryo petricola , Aloe pictifolia , Aloe pluridens, Aloe propagulif phyte ) era , Aloe reynoldsii , , Aloe saundersiae , Aloe [0170 ] The organisms of the Matricaria belong to scobinifolia , Aloe sinkatana , Aloe somaliensis , Aloe the Eukaryota superkingdom , Viridiplantae kingdom , Strep somaliensis var . somaliensis , , Aloe spicata , tophyta phylum , Asterales order and Asteraceae family . , Aloe striata subsp . karasbergensis , Aloe striata 10171 ] More preferably , the organisms of the genus Mat subsp . komaggasensis , Aloe succotrina , Aloe suprafoliata , ricaria are selected from the list consisting of: Matricaria Aloe thompsoniae , Aloe thraskii , Aloe tomentosa , Aloe chamomilla , Matricaria discoidea and Matricaria matri vaombe , Aloe variegate , Aloe vera , Aloe vera var. chinensis , carioides , or any combinations thereof. Even more prefer Aloe verecunda , Aloe viguieri , Aloe vossii , Aloe vryheiden ably , it is Matricaria chamomilla var. recutita . sis, Aloe welwitschii, Aloe x spinosissima, Aloe zebrine , or [0172 ] The organisms of the genus Thymus belong to the any combinations thereof. More preferably , it is Aloe vera . Eukaryota superkingdom , Viridiplantae kingdom , Strepto 0176 ]. In a preferred embodiment, other compounds phyta phylum , Lamiales order and Lamiaceae family . which may or may not already be present can additionally be [0173 ] More preferably , the organisms of the genus Thy added to the composition of the invention , said compound mus are selected from the list consisting of: Thymus alsi being selected from the list consisting of: caricine , emodin , noides , Thymus amurensis , Thymus broussonetii, Thymus mannose phosphate , phytosterols, plant hormones, chama broussonetii subsp . hannonis , Thymus caespititius, Thymus zulene and / or carvacrol. daenensis Thymus daenensis subsp . daenensis , Thymus (0177 ] Caricine is a chemical component stimulating the dahuricus, Thymus haussknechtii Thymus herba -barona , immune system that can be found in Aloe vera . Thymus linearis , Thymus longicaulis , Thymus magnus, Thy [0178 ] Emodin is an anthraquinone used for its laxative mus mandschuricus, Thymus marschallianus, Thymus mas properties in pharmacological treatments which at present tichina , Thymus mongolicus , Thymus oenipontanus, Thymus include severe pancreatitis . oxyodontus , Thymus paronychioides , Thymus persicus, Thy [0179 ] Mannose phosphate is useful for promoting ( speed mus praecox , Thymus praecox subsp . polytrichus, Thymus ing up ) wound healing , i. e . , it has a healing effect . proximus, Thymus pubescens, Thymus pulegioides , Thymus f0180 ] Phytosterols or plant sterols ( sterols from plants ) pulegioides var. pulegioides, Thymus quinquecostatus, Thy are natural plant- based sterols . They are organic molecules mus quinquecostatus var . przewalskii , Thymus saturejoides , that are part of the plant cell membrane, with a function Thymus saturejoides subsp . commutatus, Thymus serpyllum , similar to that of cholesterol in animal cell membranes. The Thymus sipyleus, Thymus spinulosus , Thymus striatus, Thy main effect of phytosterols is their anti - inflammatory prop mus striatus var. acicularis , Thymus striatus var. ophioliti erty so they are used in anti - aging products . In clinical cus , Thymus striatus var . striatus , Thymus trautvetteri, Thy studies , phytosterols have the property of improving dam mus vulgaris , Thymus x citriodorus, and Thymus zygioides, aged skin . or any combinations thereof. [0181 ] Plant hormones are substances produced by plant [0174 ] The organisms of the genus Aloe belong to the cells in specific locations in the plant and they regulate the Eukaryota superkingdom , Viridiplantae kingdom , Strepto physiological phenomena of plants . The main plant hor phyta phylum , order and Xanthorrhoeaceae mones that are known are : abscisic acid , auxins , cytokines , family . ethylene , gibberellins and brassinosteroids . There are other [ 0175 ] More preferably , the organisms of the genus Aloe regulator compounds that could be considered : polyamines , are selected from the list consisting of: Aloe acutissima, Aloe oxylipins , salicylates, oligosaccharins, strigolactone and africana , Aloe albida , Aloe albiflora , Aloe alooides , Aloe systemin . Specific plant hormones promote epithelization angelica , Aloe anivoranoensis , , Aloe and cell growth in humans . Chamazulene is an aromatic arborescens var. natalensis , , Aloe aristata , chemical compound having a molecular formula of C4H6 Aloe bakeri, Aloe bowiea , Aloe boylei, Aloe brevifolia , Aloe found in a variety of plants , including in chamomile (Mat broomii , Aloe buhrii , Aloe bulbillifera , Aloe cameronii, Aloe ricaria chamomilla ), wormwood ( Artemisia absinthium ), cannellii , Aloe castanea , Aloe chabaudii , Aloe challisii , Aloe and yarrow ( Achillea millefolium ) . It is an azulene derivative chortolirioides, Aloe comosa , Aloe compressa , Aloe com biosynthesized from sesquiterpene matricin . Chamazulene pressa var. compressa , Aloe conifera , Aloe conifera var. has in vivo anti- inflammatory properties . conifera , Aloe craibii , Aloe cremnophila , Aloe dawei, Aloe [0182 ] Carvacrol, or cymophenol, C H2CH3 (OH ) (C2H4 ) , deltoideodonta, Aloe dewinteri, Aloe dominella , Aloe dyeri , is a monoterpenoid phenol. It is found in essential oils such Aloe ecklonis , Aloe erinacea , , , Aloe as oregano and thyme essential oils ( 5 % and 75 % ) and forbesii, Aloe fosteri, Aloe fouriei, Aloe glauca, Aloe globu others, and is responsible for the smell. This compound ligemma, Aloe gneissicola , Aloe greatheadii, Aloe greathea - prevents infections by specific species of bacteria of the dii var. Davyana , Aloe haemanthifolia , Aloe haworthioides , genera Escherichia , Bacillus or Pseudomonas. US 2017 /0239307 A1 Aug . 24 , 2017

[ 0183 ] In another preferred embodiment, the composition [0190 ] Plant preparations include ground or crushed plant of the invention is a pharmaceutical composition . The com materials , extracts , dyes , fatty or essential oils , saps obtained positions of the present invention can be formulated for by pressing and preparations the production of which administration to an animal , and more preferably to a involves fractionation , purification or concentration . In a mammal, including humans , in a range of forms known in preferred embodiment of this aspect of the invention , the the state of the art . In this sense , these compositions can be , plant material is a plant preparation . without limitation , in a sterile aqueous solution or in bio 0191 ] A third aspect of the invention relates to the com logical fluids , such as serum . The aqueous solutions may or position of the invention for use in the relief , improvement, may not be buffered and they have additional active or prevention and /or treatment of dry eye syndrome, or alter inactive components . The additional components include natively, to the use of the composition of the invention in the salts for modulating ionic strength , preservatives including , production of a medicament for the relief, improvement, but not limited to , antimicrobial agents , antioxidants , chelat prevention and / or treatment of dry eye syndrome. ing agents, and the like , and nutrients including glucose , [0192 ] Keratoconjunctivitis sicca (KCS ) , also called dry dextrose , vitamins and minerals . Alternatively , the compo eye syndrome or keratitis sicca , is an ocular disease caused sitions can be prepared for administration in solid form . The by dryness of the eye , which is in turn caused by any compositions can be combined with several inert vehicles or reduction in the production of tears or increased evaporation excipients , including but not limited to agglutinants such as of the tear film . It is found in humans and some animals . microcrystalline cellulose , tragacanth gum , or gelatin ; KCS is the most common disease of the eye , affecting 5 - 6 % excipients such as starch or lactose ; dispersing agents such of the population . The prevalence goes up to 6 - 9 . 8 % in as alginic acid or corn starch ; lubricants such as magnesium post- menopausal women (Schaumberg et al. , 2003 . Am J stearate , glidants such as colloidal silicon dioxide ; sweeten Ophthalmol 136 ( 2 ) , 318 - 26 ) , and goes as high as 34 % in the ing agents such as sucrose or saccharin ; or aromatizing elderly ( Lin et al. , 2005 . Invest Ophthalmol Vis Sci 46 ( 5 ) , agents such as mint or methyl salicylate . 1593 ) . The Latin phrase , keratoconjunctivitis sicca means 10184 . Therefore , in a preferred embodiment of this aspect “ dryness of the ( inflamed ) cornea and conjunctiva ” . of the invention the pharmaceutical composition can further [0193 ] A preferred embodiment of this aspect of the comprise a pharmaceutically acceptable vehicle . In another invention relates to the composition of the invention for use preferred embodiment, the pharmaceutical composition fur in the treatment of dry eye syndrome associated with ther comprises excipients . In another preferred embodiment, Sjögren ' s syndrome, or alternatively , to the use of the the pharmaceutical composition can further comprise composition of the invention in the production of a medi another active ingredient. cament for the treatment of dry eye syndrome associated [0185 ] As it is used herein , the term “ active ingredient” , with Sjögren ' s syndrome . “ active substance” , “ pharmaceutically active substance” or [0194 ] A fourth aspect of the invention relates to the " pharmaceutically active ingredient” means any component composition of the invention for use in the relief, improve that may provide a pharmacological activity or another ment , prevention and treatment of Sjögren ' s syndrome, or different effect in the diagnosis , cure , mitigation , treatment, alternatively , to the use of the composition of the invention or prevention of a disease , or that affects the body structure in the production of a medicament for the treatment of or function of humans or other animals . The term includes Sjögren ' s syndrome. those components that promote a chemical change in the [0195 ] A fifth aspect of the invention relates to a dosage production of the drug and are present in the drug in an form , hereinafter dosage form of the invention , comprising envisaged modified form , providing the specific activity or the pharmaceutical composition of the invention . effect. [01961 In a preferred embodiment of this aspect , the 10186 ]. In a preferred embodiment of this aspect, the dosage form of the invention is selected from the list composition of the invention further comprises a pharma comprising: dressing , ointment, paste , cream , solution , sus ceutically acceptable vehicle . In another preferred embodi pension , emulsion , lotion , liniment, jelly , gel , foam , powder , ment of this aspect , the composition of the invention further or any combinations thereof . In another more preferred comprises another active ingredient. In another more pre embodimentof this aspect , the dosage form of the invention ferred embodiment, the composition of the invention is a is a solution , and even more preferably, an ocular solution . pharmaceutical composition . [0197 ] In this specification , " dosage form ” is understood as the mixture of one or more active ingredients with or [0187 ] A second aspect of the invention relates to the without additives having physical characteristics for suitable composition of the invention for use as a medicament, or dosing , conservation , administration and bioavailability . alternatively , to the use of the composition of the invention [0198 ] A " dressing” or “ patch ” is a dosage form consisting in the production of a medicament. of a solid or semisolid form containing the active ingredient [0188 ] As it is used herein , the term “ medicament” refers or ingredients and additives , spread on a piece of fabric , to any substance used for the prevention , diagnosis , relief, plastic or adhesive tape, acting as a support and protection , treatment or cure of diseases or their symptoms in humans in addition to having an occlusive effect and macerating and animals . action which furthermore allows it to come into direct [0189 ] Herbal medicaments are defined in this specifica contact with skin and to soften with body temperature . tion as finished and labeled medicinal products the active [0199 ] An “ unguent” or “ ointment” is a dosage form ingredients of which consist of aerial or subterranean parts consisting of a preparation having a soft consistency con of plants or other plantmaterials or combinations thereof, in taining the active ingredient or ingredients and additives crude form or in the form of plant preparations . Herbal incorporated to a suitable base giving it body and consis medicaments can also contain natural, organic or inorganic tency . It is adhered and applied to the skin and mucous active ingredients that are not plant origin . membranes . This base can be fat - or water - soluble , generally US 2017 /0239307 A1 Aug . 24 , 2017

anhydrous or with a maximum of % of water . It is also [0211 ] “ Powder" is a dosage form consisting of a solid referred to as hydrophilic unguent when it contains a base form containing the active ingredient or ingredients and that can be washed away or removed with water . additives that are finely ground and mixed to assure homo [0200 ] A “ paste” is a dosage form consisting of a semi geneity . solid form containing the active ingredient or ingredients [ 0212 ] A sixth aspect of the invention relates to a method and additives, made based on a high concentration of for producing a composition comprising the steps of: insoluble powders ( 20 to 50 % ) , in weak abrasive or absor [0213 ] a ) mixing the plant material from plants of the bent fatty or aqueous bases combined with soaps. genera Matricaria , Thymus and Aloe , the extracts of said [ 0201 ] A " cream ” is a dosage form consisting of a liquid plants , or an active ingredient obtained from said plant or semisolid preparation containing the active ingredient or material or from the extracts ; ingredients and additives required for obtaining an emul [0214 ] b ) adjusting the pH . sion , generally an oil - in -water emulsion , with a water con [0215 ] A preferred embodiment of this aspect of the tent greater than % . invention further comprises : [ 0202] A " solution ” is a dosage form consisting of a (0216 ) c ) sterilizing the solution . transparent and homogenous liquid preparation obtained by [0217 ] In another preferred embodiment of this aspect of dissolving the preparation or active ingredients and additives the invention , the mixing in a ) is performed in water or a in water and is intended for external or internal use . In the hydrate . case of injectable solutions for the eyes and ears , they must [ 0218 ] In another preferred embodiment of this aspect of be sterile . the invention , the mixing in a ) is performed in an anhydrous [ 0203 ] A “ suspension ” is a dosage form consisting of a base . dispersed system formed by two phases which contain the [0219 ] In another preferred embodiment of this aspect of active ingredient or ingredients and additives . One of the the invention , the proportion of a ) is as follows: 1 - 48 % phases, the continuous or external phase, is generally a Matricaria , 1 - 48 % Thymus and 1 -48 % Aloe . More prefer liquid or a semisolid , and the dispersed or internal phase is ably , the proportion of a ) is as follows : 3. 3 - 20 % Matricaria , made up of solids ( active ingredients ) that are insoluble but 2 .3 - 11 .1 % Thymus and 4 .4 -22 .3 % Aloe , and even more dispersible in the external phase . In the case of injectable preferably 7 .5 % Matricaria , 5 % Thymus and 10 % Aloe . suspensions, they must be sterile [0220 ] In another preferred embodiment of this aspect of [ 0204 ] An " emulsion ” is a dosage form consisting of a the invention , the pH of b ) is between 5 and 9 , more heterogeneous system generally made up of two liquids not preferably between 6 and 8 , more preferably between 7 and miscible with one another; in which the dispersed phase is 7 . 9 , more preferably between 7 . 3 and 7 . 5 , and even more formed by small globules distributed in the vehicle in which preferably 7 . 4 . they are immiscible . The dispersed phase is also known as [0221 ] The sterilization process of solution c ) can be an internal phase and the dispersion medium is known as an carried out by any sterilization method known in the state of external or continuous phase . the art . [ 0205 ] There are water- in - oil -type or oil- in -water - type [0222 ] Throughout the description and claims the word emulsions and they can be presented as semisolids or " comprises ” and variants thereof do not seek to exclude liquids . The active ingredient or ingredients and additives other technical features, additions , components or steps . can be in the external or internal phase . [0223 ] For those skilled in the art, other objects , advan [ 0206 ] A “ lotion ” is a dosage form that can be presented tages and features of the invention will be inferred in part as a solution , suspension or emulsion , containing the active from the description and in part from the practice of the ingredient or ingredients and additives, and the dispersing invention . The following examples and drawings are pro agent of which is predominantly water. vided by way of illustration and do not seek to limit the [0207 ] A “ liniment ” is a dosage form consisting of an present invention . emulsion , solution or liquid presentation containing the active ingredient or ingredients and additives the vehicle of Examples of the Invention 2 which is an aqueous , alcoholic or oily vehicle . [ 0208 ] A “ jelly ” is a dosage form consisting of a semisolid Example 1 : Preparation of the Composition colloid containing the active ingredient or ingredients and additives, the water- soluble base of which is generally made Material and Methods up of gums such as tragacanth gum , other bases used are : glycerin , pectin , alginates, boroglycerine compounds , syn [0224 ] Work was conducted in a clean room and with all thetic derivatives or natural substances such as carboxym the required measures to obtain a sterile product . ethyl cellulose . [ 0225 ] The amount of each element required for the for [0209 ] A “ gel ” is a dosage form consisting of semisolid mulation was calculated : preparation containing the active ingredient or ingredients and additives , solids in a liquid which can be water, alcohol a . Chamomile glycolic extract 7 . 5 % or oil, such that a network of particles trapped in the liquid b . Thyme glycolic extract 5 % phase is formed. c . Pulp - free aloe vera gel 10 % [ 0210 ] A " foam ” is a dosage form consisting of a semi d . Water for injection , qsf 10 ml solid preparation formed by two phases : a liquid phase carrying the active ingredient or ingredients and additives , [0226 ] The required water for injection (77 . 5 % ) is calcu and another gaseous phase carrying propellant gas for the lated . The extracts and Aloe vera gel are placed in a beaker. product to come out in the form of a cloud . 80 % of the required water for injection is added . pH is US 2017 /0239307 A1 Aug . 24 , 2017 measured . pH is adjusted to 7 . 4 with 0 . 1 N NaOH , if TABLE 1 required . The rest of the water for injection is added up to the required volume. Data on ophthalmological tests in case 1 of Sjögren ' s syndrome. [ 0227 ] It is then filtered into opaque, already sterile ves Visit on Visit on sels using a 0 .22 um filter. 17 Jun . 2014 7 Jul . 2014 [ 0228 ] A label is added which includes the composition , Schirmer, right eye 13 30 production date , expiration and any other element required Schirmer, left eye 11 25 for correctly identifying the staff preparing it and the user. It Break up time 5 > 9 is kept in the refrigerator. Hyperemia scale Grade II Grade II [0229 ] Detail of the functional active ingredients: OSDI Test 95 . 83 4 . 54 [0230 ] Chamomile flower glycolic extract : [0231 ] i. Supplier : Fagron . [0232 ] ii. Batch No . L13090187 . Example 3: Case 2 of Dry Eye Syndrome in the [0233 ] iii. INCI Composition : Propylene glycol, Context of Sjögren ' s Syndrome Aqua , Chamomilla recutita . [0259 ] Patient came on Apr. 8 , 2014 referred by the 10234 ] iv . Some physical specifications : Rheumatology Department for discomfort and itchy eyes. [ 0235 ] 1 . Relative density : 1 . 04 g /ml . She has a prior diagnosis of Sjögren ' s syndrome and has [ 0236 ] 2 . Refractive index : 1 . 393 . been treated , without showing any improvement of symp [ 0237 ] 3 . Heavy metals : < 20 ppm . toms, with lubricants , corticoids, autologous serum and [0238 ] 4 . pH : 5 . 8 cyclosporin . Visits were on the following dates: Apr. 8 , 2014 [0239 ] Thyme qlycolic extract : and Jan . 9 , 2014 [ 0240 ] v . Supplier : Metalpharmaceutical. ( A . C . E . F . ) . [ 0260 ] In the visit to the clinic on Apr. 8 , 2014 , treatment [0241 ] vi. Batch No . K2608001 was established months ago with aloe , thymus and chamo [ 0242 ] vii. INCI composition : Propylene glycol, mile eye drops after treatment with artificial tears , corti Water , Thymus vulgaris flower / extract coids , autologous serum and cyclosporin in a private center [0243 ] viii. Some hysical specifications: that have not eased the symptoms. In that center , patient was [ 0244 ] 1 . Drug/ Extract concentration : 1 : 2 proposed treatment with growth factors , which he refused . 102451 2 . pH ( 10 % solution ) : 4 . 8 Patient is examined on Jan . 9 , 2014 , and an improvement of [0246 3 . Heavy metals : < 20 ppm symptoms is seen both subjectively and objectively . A table 102471 4 . Preservatives : methyl , ethyl, propyl , containing the main parameters collected in the visit prior to butylparaben in phenoxyethanol, 0 . 2 % establishing treatment with the eye drops object of this [0248 ] Pulp - free Aloe vera gel : patent document and after treatment with aloe , thymus and [ 0249 ] ix . Supplier : Acofarma. matricaria eye drops from that visit . [0250 ] x . Batch : 140136 . 10251] xi. Some physical specifications : TABLE 2 [0252 ] 1. Density : 0 . 997 g /ml . Data on tests in case 2 of Sjögren ' s syndrome . [ 0253 ] 2 . Refractive index : 1 . 3341. [0254 ] 3 . Anthraquinones : < 0 . 1 % . Visit on Visit on [0255 ] 4 . Parenchyma/ extract ratio : 1 : 1 4 Aug . 2014 1 Sep . 2014 Schirmer , right eye O 8 [0256 ] 5 . Preservatives: potassium sorbate , sodium Schirmer, left eye 10 benzoate . Break up time Hyperemia scale Grade III Grade I Example 2 : Case 1 of Dry Eye Syndrome in the OSDI Test 100 66 . 66 Context of Sjögren ' s Syndrome [ 0257] Patient was referred by the Rheumatology Depart ment of Hospital Reina Sofia , Cordoba, for Sjögren ' s syn Example 4 : Treatment with Aloe , Matricaria and drome due to discomfort, itching and sporadic difficulty in Thymus Eye Drops in Patients with Dry Eye of any seeing to be evaluated for autoimmune dry syndrome and Origin Excluding Sjögren ' s Syndrome, and Results treatment. Patient was unsuccessfully treated with topical of the Preparation in Other Pathologies Excluding corticoids and lubricants . These visits took place on the Dry Eye Syndrome following dates : Jun . 17 , 2014 and Jul. 7 , 2014 . [ 0258 ] Patient was diagnosed in these visits with dry eye [0261 ] In patients with dry eye syndrome the standard syndrome contrasted with the original Sjögren ' s syndrome treatment of which did not ease symptoms and treatment diagnosis . In the visit to the clinic on Jun . 17 , 2014 , began with aloe, thymus and matricaria eye drops . treatment was implemented with eye drops containing aloe , [0262 ] A group of 10 patients (n = 10 ) were treated who thymus and chamomile after several treatments which did met the following criteria : not ease symptoms. Patient has a checkup on Jul. 7 , 2014 , [ 0263 ] Adult population : mean adult age of 66 years old and an improvement of symptoms is seen both subjectively ( 3 men and 7 women ) . and objectively. A table containing the main parameters [0264 ] Patients diagnosed with dry eye symptoms (ex collected in the visit prior to establishing treatment with the cluding Sjögren ' s syndrome ). eye drops object of this patent document and after 12 days [ 0265 ] OSDI ( Ocular Surface Disease Index @ ) score: of treatment with said treatment is shown below . prior mean 72. 84 . US 2017 /0239307 A1 Aug . 24 , 2017 14 .

[ 0266 ] Treatment with eye drops containing the prepara [ 0284 ] 8 . A dosage form comprising the composition tion was carried out for 21 days . The photographs in FIG . 5 according to any of claims 1 - 4 . belong to one of the 10 patients . [0285 ] 9 . The dosage form according to the preceding claim selected from the list comprising : dressing , oint Results - OSDI ment, paste , cream , solution , suspension , emulsion , [0267 ] The OSDI© (Ocular Surface Disease Index @ ) lotion , liniment , jelly, gel, foam , powder, or any combi score : evaluates on a scale of 0 to 100 the degree of nations thereof. In another more preferred embodiment of involvement of the patient, where 100 is the most severe this aspect , the dosage form of the invention is a solution , stage : and even more preferably , an ocular solution . [0268 ] Before the study, the results indicated a mean of [0286 ] 10 . The dosage form according to any of claims 72 . 84 for this indicator. 9 - 10 which is a solution . 10269] After the test, mean values dropped 75 % to 15 . 3 [0287 ] 11 . The dosage form according to the preceding being a significant improvement in 100 % of the cases . claim which is an ophthalmic solution . [0270 ] See the results in FIG . 6 . [0288 ] 12 . A method for producing an ophthalmic solution [ 0271] In patients with disorders and pathologies of comprising the following steps: another type not related to dry eye syndrome: [0289 ] a ) mixing the plant material from plants of the [0272 ] Recurring corneal ulcers : 2 cases . genera Matricaria , Thymus and Aloe , the extracts of said [0273 ] Corneal ulcers due to active VHZ (herpes ) : 2 plants , or an active ingredient obtained from said plant cases . material or from the extracts ; [0274 ] Blepharitis : 2 cases. [0290 ] b ) adjusting the pH . [0291 ] 13 . The method according to the preceding claim , [0275 ] Several conclusions can be drawn from this study further comprising: and are summarized in Table 3 : [0292 ] c ) sterilizing the solution . TABLE 3 [0293 ] 14 . The method according to claims 12 - 13 , wherein the mixing in a ) is performed in water or a hydrate . Results of applying aloe , thymus, matricaria eye drops (0294 ) 15 . The method according to claims 12 - 14 , wherein in other pathologies not associated with dry eye syndrome. the mixing in a ) is performed in an anhydrous base . Pathology Improvement [0295 ] 16 . The method according to claims 12 - 15 , wherein the proportion of a ) is as follows: 7 . 5 % Matricaria , 5 % Ulcers due Complete closure without stromal inflammatory to VHZ infiltration . Thymus and 10 % Aloe. Recurring Complete closure - active epithelization from the ulcers start. 1 - 48 . ( canceled ) Blepharitis Reduced range of the tear corneal lab from grade 49 . An ophthalmic solution comprising plant material 4 to grade 1 (normal ) . No signs of infection . from plants of the genera Matricaria , Thymus and Aloe , the 3 -month absence of symptomsmaintained . extracts of said plants , or an active ingredient obtained from said plant material or from said extracts . [ 0276 ] The following can be cited as the main achieve 50 . The ophthalmic solution according to claim 49, fur ments of the use of this treatment: strength similar to ther comprising a pharmaceutically acceptable vehicle . cortisone, astringent, anti - inflammatory, reduces hyperemia 51 . The ophthalmic solution according to claim 49 , fur to normal levels in 100 % of cases , enormous epithelization , ther comprising another active ingredient. bacteriostatic and antimycotic effect, and absence of patho 52. The ophthalmic solution according to claim 49 , logical side effects . wherein the ophthalmic solution is a pharmaceutical com position . CLAUSES 53. A dosage form comprising the ophthalmic solution [0277 ] 1 . A composition comprising plant material from according to claim 49 . plants of the genera Matricaria , Thymus and Aloe , the 54 . A method for treatment of dry eye syndrome in extracts of said plants , or an active ingredient obtained Sjögren ' s syndromepatients , the method comprising admin from said plant material or from the extracts . istering the ophthalmic solution of claim 49 to a patient in [ 0278 ] 2 . The composition according to the preceding need thereof. claim , further comprising a pharmaceutically acceptable 55 . A method for producing an ophthalmic solution com vehicle . prising the following steps: [ 0279 ] 3 . The composition according to any of claims 1 - 2 , a ) preparing a solution comprising plant material from further comprising another active ingredient. plants of the genera Matricaria , Thymus and Aloe , the [ 0280 ] 4 . The composition according to any of claims 1 - 3 , extracts of said plants , or an active ingredient obtained which is a pharmaceutical composition . from said plant material or from said extracts ; and [0281 ] 5 . Use of the composition according to any of b ) adjusting the pH of the solution . claims 1 - 4 in the production of a medicament. 56 . The method according to claim 55 , further compris [0282 ] 6 . Use of the composition of the invention in the ing : production of a medicament for the relief, improvement , c ) sterilizing the solution . prevention and treatment of dry eye syndrome. 57 . The method according to claim 55 , wherein the [0283 ] 7 . Use of the composition of the invention in the preparing in a ) is performed in water or a hydrate . production of a medicament for the treatment of the 58 . The method according to claim 55 , wherein the Sjögren ' s syndrome. preparing in a ) is performed in an anhydrous base . US 2017 /0239307 A1 Aug . 24 , 2017

59 . The method according to claim 55 , wherein the proportion of plant material is as follows: 7 . 5 % Matricaria , 5 % Thymus and 10 % Aloe . * * * * *