Pharmaceutical Solutions Comprising Dimethyl Sulfoxide

Europaisches Patentamt J European Patent Office © Publication number: 0 235 424 Office europeen des brevets A1

EUROPEAN PATENT APPLICATION

© Date of publication of application: <2) Applicant: CLARK PHARMACEUTICAL 09.09.87 Bulletin 87/37 LABORATORIES LIMITED 24 Finch Avenue © Designated Contracting States: Dowsview Ontario(US) AT BE CH DE FR GB IT LI LU NL SE @ inventor: Sandborn, Edmund 1020 White Oak Drive Burlington Ontario LTT 2L4(CA)

© An homogenous solution for topical application comprising: (a) between about 40% and about 85% DMSO by weight of the solution; (b) a polyalcohol for assisting to retain moisture in the skin and prevent the skin from dehydrating; (c) a dispersant for assisting to disperse the components in solution to provide a homogenous solution when applied and when penetrating the skin; (d) a medicine; and (e) water.

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Xerox Copy Centre 0 235 424

"PHARMACEUTICAL SOLUTIONS COMPRISING DIMETHYL SULFOXIDE"

neoplastic agents, antigens, antihistamine agents, FIELD OF INVENTION neuropharmacologic agents, anti-inflammatory agents, anticoagulants, vasodilators, ultra-violet This invention relates to novel pharmaceutical screening agents and agents with DMSO. solutions and particularly novel pharmaceutical so- 5 However, these compositions are extremely lutions comprising dimethyl sulfoxide (DMSO). greasy and are solely for surface penetration, very little penetrating deeply into affected areas where the greatest need arises. See also United States BACKGROUND OF THE INVENTION patents 3,551,554; 3,740,420; 3,743,727; 3,790,682; 70 4,369,190 and 3,499,961 and Canadian Letters Pat- If one rubs a few drops of DMSO on any part ents 1,001,075; 1,011,255; 1,043,704; 980,252 and of his/her person, it is usually absorbed very rap- 1,005,761. idly and a taste resembling garlic is immediately Furthermore these compositions are not suit- present. This finding subsequently led to a most able where there is need for rapid deep penetration important finding of pharmacologic ability of pure rs of medicine for direct application to an afflicted part DMSO of various strengths to reduce inflammation of the body O'oints etc.). In addition, DMSO also and pain in a wide range of conditions to penetrate captures water from the skin, being a hydroxyl ion into the skin after topical application of DMSO for scavenger thereby dehydrating the skin. the lessening of pain and swelling of inflammation. It is therefore, an object of this invention to Many clinicians have reported particularly gratifying . 20 provide penetrating solutions, allowing penetration results by the use of DMSO in the management of deeply into affected parts of the body, comprising arthritis. DMSO, preferably another medicine which may be United States Letters Patent 3,549,770, teaches applied topically and which rapidly penetrates the topical application of undiluted dimethyl sulfox- deeply into the body carrying the medication in the ide, and dimethyl sulfoxide with appropriate phar- 25 solutions with it while protecting the skin against maceutical diluents, excipients and adjuvants in the dehydration. treatment of tissue damage, pain, abnormal muscle Further and other objects of the invention will contraction and vascular insufficiency. be realized by those skilled in the art from the The facility with which DMSO penetrates the following summary of the invention and detailed skin and other membranes has spawned consider- 30 description of the embodiments thereof. able research into the use of DMSO as a vehicle for the administration of drugs through topical application. In the course of that research a number SUMMARY OF THE INVENTION of different products were added to DMSO with ranging degrees of success. 35 According to one aspect of the invention, a United States Letters patent 3,711,606 teaches deeply and rapidly penetrating homogeneous solu- the use of DMSO as a carrier in concentrations of tion for topical application causing medicine to pen- 50% and over by weight with a steroid in lotion, etrate deeply and rapidly into affected parts of the cream, gel and ointment forms to penetrate rapidly body without irritating the skin or leaving a greasy to and saturate the stratum comeum, the highly 40 film on the skin when the solution is applied topi- resistant "horny layer" of the skin which is the cally is provided, the solution comprising: major barrier to penetration. (a) between about 40% and about 85% According to this patent "The Steroid continues DMSO by weight of the solution, more preferably to penetrate through the skin from 'this reservoir' in between about 60% and about 70% DMSO by the stratum corneum to the underlying tissue and 45 weight of the solution and most preferably about into the circulatory system" (Column 3 line 50 - 65% DMSO ■..■! weight of the solution; 53). (b) a polyalcohol, preferably having 3 -5 car- United States Patent 3,711,602 also teaches bon atoms, for the retention of moisture in the skin, the compositions (creams, suppositories, ointments in one embodiment, glycerol or glycerine; and gels) for topical application for enhancing tis- so (c) A dispersant for assisting to disperse the sue penetration of physiologically active agents (for components in solution to provide a homogeneous example, physiologically active steroids, anti- solution when applied to the skin and when penetrating the skin, in one embodiment propylene glycol; 0 235 424

(d) a medicine for example naproxen and Solution as a treatment for psoriasis diclofenac dissolved in the solution; (e) water. 65 ml 90% DMSO Because the medicine must be dissolved in the 3.375 gm diclofenac solution, a solubilizing agent may be added to the 5 80 ml H2O solution to dissolve the medicament. For example, 5 ml 2% xylocaine naproxen is not soluble in DMSO. Therefore, 250 ml ethyl alcohol ethanol is used to solubilize the naproxen for addi- 65 ml glycerine tion to the solution. Xylocaine may also be added 30 ml propylene glycol to the solution where desired. 10 5 ml tar When the penetrating solutions of the invention are employed in topical applications unexpected results from treatment therewith are obtained. This DMSO with diclofenac and urea as a treatment for is because of the ability of the solution to penetrate arthritis with added skin protection. quickly and deeply into the body through the skin 75 and tissue below the point of topical application. 325 ml DMSO 90% Furthermore, because of the nature of the solution, 70 ml H2O the skin is not dried out. Where glycerol is em- 50 gm urea ployed, glycerol is a hydroxyl radical scavenger (as 25 ml glycerine is DMSO) and assists in the medicinal effect of the 20 75 gm diclofenac DMSO in the solution. The dispersant propylene 25 ml propylene glycol glycol is also a hydroxyl radical scavenger. The formulations are prepared by combining the requisite amounts of the ingredients together - Solution for treatment of herpes (adding solubilizing agents, for example ethanol 25 where naproxen is to be included). The medicines 335 ml DMSO 90% that may be used with the DMSO may be manufac- 25 ml glycerol tured according to the processes taught in the 25 ml propylene glycol following patents or other such suitable processes: 100 ml H2O NAPROXEN: Canadian Letters Patents 1,122,603; 30 15 ml ethyl alcohol 1,004,226; 1,142,957; 1,137,108; 879,118; 879,719; 75 gm diclofenac 936,171; 955,600; 960,668; 960,689; 983,517; The following case histories are offered where 991,655; 1,000,725; 1,000,726; 1,020,575; and penetrating solutions according to the invention 1,124,735. DICLOFENAC: Canadian letters patents were employed. 850,133; 811,738; 829,910; 918,175; 765,432; 35 In each of cases 1 to 8 inclusive the anti- 827,708; 1,126,746; and 1,050,565. NIFEDIPINE: inflammatories used were naproxen or diclofenac. Canadian Letters Patents 981,582; 934,758; 868,91 1 ; 921 ,035; and 1 ,080,2 Triethanolamine salicylate may also be used. Case 1. Mrs. E.G. -Age 58 Years -Rheumatoid The invention will now be illustrated having 40 Arthritis regard to the following embodiments and exem- plary test cases. Severe pain in left tarsal joint, then late in May, right foot then rapidly involved right leg, both shoulders, elbows and wrists. Was first treated with EMBODIMENTS 45 phenylbutazone, then naproxen, but four months later was becoming severely disabled with acute DMSO with diclofenac as a treatment for arthritis. symptoms, particularly shoulders, wrists, and right foot -33 joints involved. Thereafter, treatment with 300 ml 90% DMSO penetrating solution comprising DMSO with 60 ml glycerine so naproxen, ethanol, water, propylene giycol and 25 ml propylene glycol glycerine by the topical application thereof. Indocid 100 ml water was administered by mouth. By the next month 15 ml ethyl alcohol some improvement in mobility, but shoulders still 75 gm diclofenac only slight (10) abduction. Treatment was contin- 55 ued five times daily. Three months later remarkable improvement in mobility. Three months later, returned to work part-time. 0 235 424

This patient has shown steady improvement exacerbations of acute arthritis his mobility has with essentially full return to range of motion in ail increased until he can walk much better. Lifestyle joints. Still employs DMSO by itself for fiare-ups. closer to normal. Can go without medication.

Case 5. Mr. M.L. -Age 51 Years -Osteoarthritis Case 2. Mrs. B.W. -Age 52 Years -Post Traumatic Arthritis Right knee -began following a football injury 30 years ago. Had meniscus excised. Activities quite Ankle-skiing accident with comminuted frac- w limited due to pain. Began topical application of ture. Repaired by surgical intervention with nu- penetrating solution comprising DMSO, anti-inflam- merous screws and plates-on screw later removed. matory, propylene glycol, glycerine and water. Ex- After 13 years of restricted movement and acute ercise tolerance and comfort improved steadily. pain, patient was advised that if she was not pre- Patient has been able to participate in sports in pared to tolerate the pain, the only alternatives 75 more comfort. were fusion or amputation. Began trial with topical application of a penetrating solution of DMSO anti- inflammatories, propyiene glycol, water and glyc- Case 6. Mr. K.L. -Age 62 Years -Osteoarthritis erine. Within days mobility began to improve and this was gradually followed by a reduction in pain. 20 Knees. Has had one cartilage removed. Unable Four months later almost complete return of func- to participate in sports without pain. Began topical tion and was pain-free. Now only employs DMSO application of formulation used in Case 1. In- at irregular intervals. creased ability to participate in sports. Improve- ment still maintained in spite of acute flare-ups on 25 occasion. Case 3. Mrs. J.F. -Age 52 Years -Traumatic Arthri- tis Case 7. Mr. B.P. -Age 59 Years -Acute Bursitis and Fractured left ankle on three occasions -each Arthritis repaired by open reduction. Movements severely 30 restricted and pain severe. Employed crutches -has Acute Bursitis left shoulder. Abduction only done for so three years. Began topical treatment 150. Acute pain in both knees from degenerated with formulation used in Case 1. After treatment, cartilages and osteoarthritis. Patient began topical and comfort flexibility both improving -can bear treatment with penetrating solution comprising A some weight. month later flexibility improving but 35 DMSO, anti-inflammatory, propylene glycol, glyc- still a long way to go. However, lateral and medial erine and water after arthroscopy and by the time of movement tarsal joints had improved consider- his surgical booking had arrived, he was so much but ably dorsiflection still quite limited. Four improved he refused the surgical procedure. His months later could finally touch heel to floor. Some pain gradually receded, mobility of knees and months later, ankle greatly improved. Both mobility 40 shoulder increased until he was able to live in and improved pain quite tolerable. Has been able comfort and return to active work and sports with- to live normally, walks, dances, etc. Has had bouts out pain. He now only requires occasional applica- of gouty arthritis in other foot but this is also under tion of DMSO solution for slight discomfort. satisfactory control. 45 Case 8. Age 64 Years Case 4. Mr. H.B. -Age 63 Years -Arthritis Patient diagnosed as having neuromuscular Arthritis in wrists, hands, feet ankle, and back. rheumatism and advised prolonged bed rest -sug- Arthritis recurrent exacerbations. for 22 years. 50 gested period, three years. Patient has marked Has reached the point where wrists and ankles are crepitus joints. Had been told 'her chances of work- almost completely ankylosed -very little movement ing again were non-existent' (Mayo Clinic). Patient obtainable. Is able not to continue at work. Barely was a practical nurse who had re-entered a regis- able to walk. Began topical application of penetrat- tered nursing training course but was forced to -solution ing comprising DMSO anti-inflammatory, 55 stop due to illness. When first seen was in a wheel propylene gfycol, glycerin and water. Improvement chair and even had great difficulty in swallowing. was seen quite rapidly by reduction of effusion and After treatment with penetrating solution comprising slow increase of mobility over the years. In spite of DMSO, anti-inflammatory, propylene glycol, glyc- 0 235 424

erin and water for several days, a slight increase in pylene glycol and distilled water, there was a very movement of joints was detectable. A month later, marked improvement over the first four months. felt immensely better and flexion and rotation of Now she uses the solution on a prn basis. shoulders had increased dramatically. She had an excellent response. Subsequently returned to nurs- 5 ing school. Works three nights a week and has Case 1 1 . returned to driving an automobile. This patient has obtained full function of joints and muscles. Has Patient was in extreme pain from post herpetic completed her nursing training and has worked full- neuritis. She had a band of scars C8 to T3 -medial time since. She has now entered the B.Sc. nursing io arm, back, exilla and upper breast. Patient had a training course and is doing very well. previous history of Graves Disease and cancer of As many changes can be made to the embodi- the bladder. After treatment with the penetrating ments disclosed without departing from the scope solution of dimethyl sulfoxide, triethanolamine sali- of the invention, it is intended that all material cylate, glycerine, propylene glycol and distilled wa- contained herein be interpreted as illustrative of the 75 ter, within two weeks there was great improvement invention and not in a limiting sense. of post herpetic neuritis. After one week only itchi- ness and tenderness remained.

SUPPLEMENTARY DISCLOSURE 20 Case 12. Applicant has also found triethanolamine salicylate to be a suitable medicine. Patient was diagnosed as having post herpetic One formulation found suitable was neuritis left forearm and hand. She had had this 315 ml 90% dimethyl sulfoxide condition for seven years duration. After treatment 40 ml glycerine 25 with a penetrating solution of dimethyl sulfoxide, 45 ml propylene glycol diclofenac, glycerine, propylene glycol, and dis- 100 mi distilled water tilled water, there was considerable improvement. 52 g triethanolamine salicylate. However, after treatment with the penetrating solu- The following case histories are offered where tion of dimethyl sulfoxide, triethanolamine salicy- penetrating solutions according to the invention 30 late, glycerine, propylene glycol and distilled water, were employed. there were excellent results.

Case 9. 13. 35 Patient was diagnosed as having chon- Patient was diagnosed as having rheumatoid dromalacia and osteoarthritis in the knee of many arthritis since 1974. The patient had extreme defor- years duration. She had considerable limitation of mity of the wrists, hands, knees and elbows with movement and pain. Crepitations felt on knee rheumatoid nodules on forearms and elbows. After movements. After treatment with penetrating solu- 40 treatment with both (a) dimethyl sulfoxide, diclofen- tion comprising dimethyl sulfoxide, triethanolamine ac, glycerine, propylene glycol, and distilled water salicylate, glycerine, propylene glycol and distilled and (b) dimethyl sulfoxide, triethanolamine salicy- water for about four months, the knee was greatly late, glycerine, propylene glycol, and distilled wa- improved and pain relieved. While the knee was ter, great improvement in mobility and comfort was still slightly stiff, mobility was greatly improved. Her 45 the result. He has returned to work as a furniture knee was still slightly affected by the weather. restorer, something he was unable to do for some time before the treatments.

Case 10. 50 Case 14. Patient was diagnosed as having arthritis in her left knee of many years duration. After treatment The patient, a former football player, was di- with the penetrating solution comprising dimethyl agnosed as having osteoarthritis of the knee and sulfoxide, triethanolamine salicylate, glycerine, pro- ankle, chondromalacia. The patient had arth- 55 roscopic removal of part of his semilunar cartilages. He was in extreme pain, unable to continue playing golf or other activities for a period of at least two years prior to treatment. After treatment with 0 235 424 10

dimethyl sulfoxide, triethanolamine salicylate, glycerine, propylene gFycol, and distilled water, even through there was X-ray evidence of moderate de- generation of knee cartilages, he has improved his range of mobility and comfort to the extent that he is now able to golf 18 holes regularly.

Claims i 10 1. A deep and rapidly penetrating homogenous solution for topical application causing medicine to penetrate deeply into affected parts of the body without irritating the skin or leaving a greasy film on the skin when the solution is applied topically, 15 the solution comprising: (a) between about 40% and about 85% DMSO by weight of the solution; (b) a polyalcohol for assisting to retain moisture in the skin and prevent the skin from dehydrat- 20 ing; (c) a dispersant for assisting to disperse the components in solution to provide a homogenous solution when applied and when penetrating the skin; 25 (d) a medicine; and (e) water. 2. The solution of Claim 1, wherein the medicine is selected from (a) Naproxen, ethanol being added as a solubilizing agent, (b) Nifedipine, (c) 30 Diclofenac, (d) Triethanolamine, (e) Triethanolamine salicylate. 3. The solution of Claim 1 or Claim 2 wherein the polyalcohol has 3-5 carbon atoms. 4. The solution of Claim 3, wherein the polyal- 35 cohol is glycerol (glycerine). 5. The solution of any preceding claim, wherein the DMSO is present between about 60% and about 70% by weight of the solution. 6. The solution of Claim 5, wherein the DMSO 40 constitutes about 65% by weight of the solution. 7. The solution of any preceding claim, wherein the dispersant is propylene glycol.

55 M European Patent Application number EUROPEAN SEARCH REPORT Office EP 86 30 1657

DOCUMENTS CONSIDERED TO BE RELEVANT Citation of document with indication, where appropriate, Relevant CLASSIFICATION OF THE Category of relevant passages to claim APPLICATION (Int. Cl A)

EP-A-0 051 163 (F. KOHLER 1,3-7 A 61 K 47/00 CHEMIE KG) A 61 K 9/08 * Claims *

D,Y US-A-4 353 896 (M.A. LEVY) 1-7 * Claims 2-10 *

D,A US-A-4 369 190 (T.L. SCHULTE) 1-7 * Claims *

A CHEMICAL ABSTRACTS, vol. 101, 1,3-7 no. 18, October 1984, page 343, abstract no. 157542e, Columbus, Ohio, US; S.A. IBRAHIM et al . : "Solubility of acetazol amide and chlorthalidone in mixed aqueous solvent system", & PHARM. IND. TECHNICAL FIELDS 1984, 46(4), 412-16 SEARCHED (Int. Cl") * Whole abstract * A 61 K

The present search report has been drawn up for all claims Place of search Date of completion of the search Examiner THE HAGUE 28-10-1986 BERTE M.J.

CATEGORY OF CITED DOCUMENTS T : theory or principle underlying the invention E : earlier patent document, but published on, or X particularly relevant if taken alone after the filing date Y : particularly relevant if combined with another D : document cited in the application document of the same category L : document cited for other reasons A : technological background O : non-written disclosure & member of the same patent family, corresponding P : intermediate document - document