3,549,746 United States Patent Office Patented Dec. 22, 1970 1. 2 3,549,746 methyl-4-isoxazolylpenicillin, dicloxacillin 3-(2,6 - di ANTBOTC COMPOSITION chlorophenyl) - 5 - methyl - 4 - isoxazolylpenicillin) and Alphonse Peter Granatek, Baldwinsville, Bernard Charles flucloxacillin 3-(2-chloro-6-fluorophenyl) - 5 - methyl Nunning, Liverpool, Nicholas George Athanas, East 4-isoxazolylpenicillin include the free acid forms and the Syracuse, Robert Lewis Dana, Liverpool, Edmund nontoxic, pharmaceutically acceptable cationic salts of Stanley Granatek, Baldwinsville, and Raymond George those penicillins and the anhydrates and hydrates of those Daoust, DeWitt, N.Y., assignors to Bristol-Myers Company, New York, N.Y., a corporation of Delaware penicillins. The preparation and properties thereof have No Drawing. Filed Nov. 2, 1967, Ser. No. 679,982 been described, inter alia, in U.S. Pats. 2,996,501, 3,239,- int, C. A61k 27/00 507 and 3,317,389. U.S. C. 424-35 10 Claims O As used herein the term nafcillin (2-ethoxy-1-naphthyl penicillin) includes the free acid form and the nontoxic, pharmaceutically acceptable cationic salts of the peni ABSTRACT OF THE DISCLOSURE cillin and the anhydrates and hydrates of the penicillin. A pharmaceutical composition in unit dosage form com The preparation and properties thereof have been de 15 scribed, inter alia, in U.S. Pat. 3,157,639. prising coated particles of certain penicillins such as di Ampicillin is the generic name for D-(-)-a-amino cloxacillin, the coating comprising ethylcelluose and a benzylpenicillin. As used herein, the term amplicillin in pharmaceutically acceptable wax; and a pharmaceutical cludes the free acid (i.e., amphoteric) form, the anionic carrier when administered orally to animals including man salts with acids such as hydrochloric acid, and cationic is useful in the treatment of bacterial infections. 20 salts with bases such as sodium hydroxide and the anhy drates and hydrates of that penicillin. Their preparation and properties have been described, inter alia, in U.S. BACKGROUND OF THE INVENTION Pats. 2,985,648, 3,140,282, 3,144,445 and 3,157,640 and (1) Field of the invention in an application of our colleagues Herbert H. Silvestri and This invention relates to novel antibacterial compo 25 David A. Johnson filed Oct. 29, 1962 as U.S.S.N. 233,943 and issued Apr. 27, 1965 as U.S. Pat. 3,180,862. sitions for oral administration. More particularly this in Hetacillin is the generic name for 6-(2,2-dimethyl-5- vention relates to novel pleasant tasting penicillin compo oxo-4-phenyl-1-imidazolidinyl) penicillanic acid which has sitions in unit dosage form which are useful for treating the structure bacterial infections in animals including man. 30 (2) Description of the prior art Penicillins have been used with considerable success in { X-r-g-oEN N–CH-cí s Yo/CH, on the treatment of bacterial infections in man. Unfortunately some of the penicillins and in particular the isoxazolyl Y/ C-N-CHCOO series of penicillins e.g. oxacillin, cloxacillin, dicloxacillin 35 and flucloxacillin as well as nafcillin and to some extent As used herein, the term hetacillin includes the "free acid' ampicillin and hetacillin have an extremely bitter taste. illustrated above and its nontoxic, pharmaceutically ac The taste has been difficult to mask by the mere addition ceptable cationic salts of the acidic carboxylic acid group of flavoring or sweetening agents. Therefore there exists 40 and its nontoxic, pharmaceutically acceptable acid addi a need for more palatable penicillin products for oral ad tion anionic salts (ie., salts of the basic nitrogen), and ministration containing these unpleasant tasting penicillins. the anhydrates and hydrates of that penicillin. Their prepa Thus an object of the present invention is to provide pala ration and properties are described in Belgian Pat. 642,851 table penicillin compositions useful for oral administra and in an application of our colleagues David A. Johnson tion in the treatment of bacterial infections in man. 45 and Charles A. Panetta filed January 6, 1965, as U.S.S.N. 423,677 and issued Aug. 3, 1965, as U.S. Pat. 3,198,804. SUMMARY OF THE INVENTION The waxes useful in the coatings with ethylcellulose The composition of the present invention comprises are the water insoluble pharmaceutically acceptable waxes coated particles of a penicillin selected from the group including paraffin wax, ozokerite wax, ceresin wax, Utah consisting of ampicillin, hetacillin, nafcillin, oxacillin, 50 wax, montan wax, carnauba wax, Japan wax, bayberry cloxacillin, dicloxacillin, and flucloxacillin and mixtures wax, flax wax, candelilla wax, sugar cane wax, spermaceti thereof and a pharmaceutical carrier, wherein said coating wax, beeswax, Chinese wax, shellac wax, Castorwax (hy comprises ethylcellulose and a pharmaceutically acceptable drogenated castor oil), and the like. A single Wax or Wax. mixture of waxes can be used. A preferred Wax is sper DETALED DESCRIPTION 55 maceti wax and a preferred mixture of waxes is spermaceti wax and CastorWax. The compositions of this invention are suitable for oral The penicillins used in the compositions of this in administration to man. They are palatable and the peni vention are conveniently coated by a process which con cillin contained therein is readily absorbed. The penicillin prises suspending micronized particles of the penicillin in contained in the compositions is absorbed from the hu 60 a solution of the coating material in a nonreactive volatile man gastrointestinal tract upon oral administration, sub organic solvent, spray drying the suspension and recover stantially at the same rate as from like compositions con ing the coated penicillin particles. However any of the taining the uncoated penicillin. This property of the com conventional coating methods can be used. positions of this invention was totally unexpected in view In carrying out the process, a suspension of micronized of the teachings of various patents e.g. U.S. 2,805,977 that 65 particles of the penicillin in a solution containing ethyl coating of medicaments with similar coating materials cellulose and a pharmaceutically acceptable wax in a non produces delayed release of the medicament. In treatment reactive volatile organic solvent or mixture of solvents is of bacterial infections it is desirable to quickly attain a spray dried by spraying the suspension into a heated non blood level of the penicillin sufficient to combat the bac reactive gaseous medium to remove the solvent. The Sus terial infection. 70 pension contacts the gaseous medium as finely divided As used herein the terms oxacillin (3-phenyl-5-methyl droplets. The term micronized as used herein means a 4-isoxazolylpencillin), cloxacillin (3-(3-chlorophenyl)-5- particle size not greater than 30 microns. 3,549,746 3 4. The suspension of sodium dicloxacillin is sprayed into organisms; and the oxacillin, dicloxacillin, flucloxacillin, a gaseous medium, e.g. air, having a temperature of about nafcillin and cloxacillin compositions are particularly 240° to 260 F. preferably about 250 F. to rapidly effective against Gram-positive bacteria including espe vaporize the solvent. The vaporized solvent is removed by cially those resistant to benzylpenicillin. the gaseous medium. The compositions are administered in the same dosage The solvent used to dissolve the coating material is as other oral preparations containing the same penicillins, vaporized and removed during spray drying. Thus the sol e.g. dicloxacillin. Thus, for children the composition may vent must be volatile. Representative of useful solvents be administered to provide daily about 50 mg. ampicillin include methylene chloride, chloroform, cyclohexane, or cloxacillin or oxacillin, or 25 mg. of hetacillin or carbon tetrachloride, methylethylketone, acetone, and the nafcillin or 12.5 mg. of flucloxacillin or dicloxacillin per like. The preferred solvent is methylene chloride. O kg. of body weight per day given in three or four divided The coated penicillin particles contain from about 7 doses. For adults the composition may be administered to parts by Weight of coating material per part by weight of provide daily about 1. g. of amplicillin or cloxacillin or penicillin to about 9 parts by weight of penicillin per part hetacillin, or nafcillin or 2 g. oxacillin or 500 mg. of of weight of coating material. The coated penicillin dicloxacillin or flucloxacillin given in three or four divided particles preferably contain about 1 to 3 parts by weight doses in dosage units of for example 125 or 250 or 500 of coating material per part by weight of penicillin and mg. of penicillin. Oral suspensions containing from about in the most preferred embodiment 3 parts by weight of 50 to about 125 mg. of penicillin and preferably from coating material per part by weight of penicillin. The about 60 to 70 mg. of penicillin per teaspoonful are coating preferably contains about 1 to 3 parts by weight 20 convenient dosage forms. In particularly severe infections of Wax or mixture of waxes per part by weight of ethyl the foregoing dosages are doubled. cellulose. The following examples are intended to illustrate the While the coating of the penicillins must contain ethyl invention claimed herein without unduly restricting it. cellulose and a pharmaceutically acceptable wax to achieve its desired properties, other coating materials can 25 EXAMPLE 1. also be included e.g. hydrogenated peanut oil, cetyl alcohol, hydrogenated vegetable oil and the like. Spray coated ethylcellulose-spermaceti The following combinations of coating materials are sodium dicloxacillin particularly useful: ethylcellulose-spermacetic wax, ethyl Formula cellulose-beeswax-Castorwax-cetyl alcohol, ethyl-cellulose 30 CastorWax-hydrogenated peanut oil-hydrogenated vegeta Amounts for 1000 grams ble oil with lecithin-sesame oil, ethylcellulose-paraffin wax, Sodium dicloxacillin, micronized ------grams. 250.0 and ethylcellulose-spermacetic-Castorwax-paraffin wax. Ethylcellulose (viscosity 100 cps.) ------do---- 250.0 The coated penicillin particles for use in the composi Spermaceti wax ------do---. 500.0 tions of this invention have a size not larger than 40 mesh Methylene chloride ------liters-- 15.0 (U.S.) and particles having a size of not larger than 150 mesh (U.S.) are preferred. Manufacturing instructions In a preferred embodiment of the present invention (1) Dissolve the spermaceti wax in approximately 8 dicloxacillin coated with ethylcellulose and spermaceti liters of methylene chloride. The operation is carried out Wax is empolyed in the composition. In the preparation 40 in a 20 liter glass or stainless steel container with the of the coated dicloxacillin, a suspension comprising aid of a mixer (e.g. a Lightnin mixer). No heat is re dicloxacillin ethylcellulose, spermaceti wax and methylene quired. chloride is sprayed into air at about 250° F. Ethylcellulose (2) To the clear solution obtained in Step + 1, add and Spermaceti wax are present in the suspension in the the ethylcellulose in small portions while maintaining proportion of 1 part by weight per part by weight of 45 agitation. Stir until a clear and relatively viscous solu Sodium dicloxacillin and 2 parts by weight per part by tion is obtained. Weight of sodium dicloxacillin respectively. The solvent, (3) The Sodium dicloxacillin is then added in small methylene chloride, is present in the proportion of from portions while maintaining agitation. A milky white sus about 7% to 15 liters per kilogram of sodium dicloxacillin, pension will result, ethyl cellulose and spermaceti wax. The suspension flow 50 (4) Strain the solution obtained in Step #3 through rate is adjusted to obtain proper evaporation of the three layers of cheesecloth if necessary to remove any methylene chloride. particulate contaminants. The compositions of the present invention are provided (5) The remainder of the methylene chloride (7 liters) for administration to animals in solid and liquid unit is then added while agitation is maintained and complete dosage forms, Such as tablets, capsules, powders, pills, 5 5 dispersion of the Sodium dicloxacillin is effected. The granules, syrups, elixirs and the like. Suitable carriers for dispersion must be free from small lumps or agglomerates. use in the compositions are gelatin capsules, sugars, cellu (6) The Nerco-Niro Laboratory model spray drier is lose derivatives, such as sodium carboxymethyl cellulose, readied as follows for the following conditions: gelatin, talc, magnesium sterate, vegetable oils such as Note: Assemble completely before starting except for peanut oil, etc., liquid petroleum, glycerin, sorbitol, the atomizer. ethanol, agar, Water and the like. The compositions can 60 also contain Suitable preservatives, coloring and flavoring (a) Turn on the electric heater to setting #2 or 3 until agents. The carrier may serve as a binder and the com the inlet air gauge reads around 130° C. position may be tabletted. If the carrier is a gelatin capsule, (b) When equilibrium is reached: the coated penicillin may be encapsulated into the gelatin The inner air gauge will read-115°-120° C. capsule by conventional means. If a liquid carrier is used, The outlet air gauge will read-50°-55° C. the composition may be in the form of a suspension. (c) Install the turbine atomizer in its proper position The compositions of this invention offer all of the Over a Teflon gasket and feed compressed air until the established therapeutic benefits of other oral preparations atomizer gauge reads 6 kg/cm.2. At this point maximum of the specified penicillins, e.g. dicloxacillin. Thus, they 70 compressed air pressure is in use (90-100 lbs.) and the may be used for the control of infections sensitive to the turbine is turning at a rate of 40,000 r.p.m. Allow 5 min Specified penicillins, e.g. dicloxacillin sensitive organisms utes for equilibrium in the chamber before liquid feeding causing respiratory tract infections. The ampicillin and is commenced. hetacillin compositions of this invention are effective (d) Start liquid feed to the turbine from a 2 liter against Gram-positive as well as many Gram-negative 75 Separatory funnel connected to the turbine by a short 3,549,746 5 6 piece of Teflon tubing. Feed at a rate of 60 ml. to 80 ml. Manufacturing instructions per minute. (1) In a suitable stainless steel container and with (e) Monitor the operation to maintain the following the aid of a mixer, (e.g. a Lightnin mixer) dissolve the drying conditions throughout the entire operation: spermaceti and the Castorwax with methylene chloride. Inlet air: 115-120° C. 5 If necessary use steam as a heat source in order to main ‘Outlet air: 60-70' C. tain a temperature of about 25° C. and facilitate dis solution of the Castorwax. (f) Stop the atomizer and turn the electric heater to (2) To the clear solution obtained in Step it 1, add position M (exhaust fan). Allow 5 minutes in this posi the ethylcellulose in small portions while maintaining tion before lifting cover. O agitation until a clear viscous solution is obtained. (g) Lift cover with the aid of the hydraulic lift and (3) To the solution in Step it 2 add the sodium diclox collect product from the walls. acillin in small portions while maintaining agitation. Con (h) The product is not expected to stick to the walls tinue mixing until a milky white suspension is obtained. of the chamber other than by electrostatic forces. It must be free from lumps or small aggregates. (i) Dry product in vacuum oven overnight at room (4) Pass the solution obtained in Step #3 through temperature. The methylene chloride residue is less than three layers of cheesecloth if necessary in order to re 0.5%. move particulate contaminants. (j) The free flowing coated sodium dicloxacillin (5) Transfer the dispersion from Step #4 into the product is passed through a 40 mesh screen and collected. Graco pump and spray gun assembly (Monarch model). EXAMPLE 2. Connect the pump to the 100 lbs. compressed air supply Spray coated sodium dicloxacillin for oral suspension, and circulate the dispersion for at least 5 minutes by 62.5 mg./5 ml. (ethylcellulose-spermaceticoating) manually adjusting the air pressure to 60 lbs. (6) Fit the Graco spray gun with tip iDLN-C1150 Formula Per 60 m. (.011'). Sodium dicloxacillin (spray coated (7) Assemble the Nerco-Niro Laboratory spray drier ethylcellulose - spermaceti from completely with the exception of the air driven atomizing Example 1) ------0.825 gram (di turbine and establish the following temperature equi cloxacillin activ librium: ity), 3.7 g. 30 Inlet air: 115-120° C. Sodium cyclamate ------2.400 grams. Outlet air: 45-50° C. Sodium Saccharin ------0.400 gram. (8) Remove the porthole from the side of the spray Sodium citrate, anhydrous ------0.420 gram. drier, insert the spray gun and activate the gun main Sodium benzoate ------0.060 gram. taining constant spraying. Sodium chloride ------1.200 grams. 35 (9) Occasionally inspect the gun for clogging, re Gum tragacanth ------0.425 gram. move and clean tip if necessary. Kaolin ------6.000 grams. (10) Collect the product and dry in the vacuum oven Sucrose, 30 mesh ------25.000 grams. at room temperature overnight. The methylene chloride Dye ------0.500 gram. residue is less than 0.5%. Flavors ------0.930 gram. 40 (11) The free flowing coated sodium dicloxacillin 1. This figure represents dicloxacillin activity and includes 10% excess. To calculate the amount of sodium dicloxacillin product is passed through a 40 mesh screen and collected. to be used, apply the following formula : EXAMPLE 4 0.825X1000 Grams coated sodium Spray coated sodium dicloxacillin powder for oral sus Potency of coated sodium 'dicloxacillin to use pension 62.5 mg./5 ml. (ethylcellulose-spermaceti dicloxacillin in mcg../mg. per bottle. Castorwax coating) Manufacturing instructions Formula Per 60 m. (1) Mix all of the ingredients except the spray coated Sodium dicloxacillin (spray coated sodium dicloxacillin and the kaolin with approximately ethylcellulose - spermaceti-Castor one-third of the sucrose in a suitable blender. Mix for 50 Wax from Example 3) ------0.825 gram. 30 minutes. (dicloxacillin (2) Add the blend from Step #1 to the remainder of activity), 3.7 g. the sucrose and add the kaolin. Mix for 30 minutes. Sodium cyclamate ------2.400 grams. (3) Add the spray coated sodium dicloxacillin to the Sodium Saccharin ------0.400 gram. blend in Step 2 and mix for 30 minutes. Sodicm citrate, anhydrous ------0.420 gram (4) Fill into 3 oz. round flint bottles. Sodium benzoate ------0.060 gram. Reconstitution: Add a sufficient volume of distilled Sodium chloride ------1.200 grams. water to make 60.0 ml. This will yield a suspension hav Gum tragacanth ------0.425 gram. ing 10% over the label claim potency of 62.5 mg. per Kaolin N.F. ------NN- 6.000 grams. 5 ml. of sodium dicloxacillin activity. 60 Sucrose, 30 mesh ------25.000 grams. Dye ------0.500 gram. EXAMPLE 3 Flavors ------0.930 gram. Spray coated ethylcellulose-spermaceti-Castorwax-sodium This figure represents dicloxacillin activity and includes dicloxacillin a 10% excess. To calculate the amount of sodium dicloxacillin to be used, apply the following formula: Formula 65 Amount per 0.825X1000 Grams coated sodium 1000 grams Potency of coated sodium dicloxacillinto use Sodium dicloxacillin, micronized ------grams. 250.0 dicloxacillin in mcg../mg. per bottle. Ethylcellulose (viscosity 100 c.p.s.)------do---- 250.0 Manufacturing instructions Spermaceti Wax------do---- 416.5 70 (1) Mix all of the ingredients except the spray coated Castorwax (melting point 85 C.)------do---- 83.5 Sodium dicloxacillin and the kaolin with approximately Methylene chloride ------liters 7.575 one-third of the sucrose in a suitable blender. Mix for Note: The preparation must be kept at a temperature 30 minutes. of 20° to 25 C. to prevent the waxes from precipitating (2) Add the blend from Step #1 to the remainder of out of solution. 75 the sucrose and add the kaolin. Mix for 30 minutes. 3,549,746 7 8 (3) Add the spray coated sodium dicloxacillin to the Formula blend in Step #2 and mix for 30 minutes. Per 60 m1. (4) Fill into 3 oz. round flint bottles. Sodium dicloxacillin (spray Reconstitution: Add a sufficient volume of distilled coated ethylcellulose-bees water to make 60.0 ml. This will yield a suspension hav 5 wax - Castorwaxcetyl alco ing 10% over the label claim potency of 62.5 mg. per hol from Example 5).---- 0.825 gram (dicloxacillin 5 ml. of sodium dicloxacillin activity. activity), 3.7 g. Sodium cyclamate ------2.400 grams. EXAMPLE 5 Sodium saccharin ------0.400 gram. Spray coated ethylcellulose-Castorwax-beeswax-cetyl al O Sodium citrate, anhydrous -- 0.420 gram. cohol-sodium dicloxacillin Sodium benzoate ------0.060 gram. Sodium chloride ------1.200 grams. Formula Gum tragacanth, Soluble Amounts per Product Corp. ------0.425 gram. 1000 grams 15 Kaolin ------6.000 grams. Sodium dicloxacillin, micronized ------grams. - 250.0 Sucrose, 30 mesh ------25.000 grams. Ethylcellulose (viscosity 100 cps.) ------do...-- 250.0 Dye ------0.500 gram. Castorwax (melting point 285 C.) ------do. --- 100.0 Flavors ------0.930 gram. Beeswax ------do---- 300.0 - This figure represents dicloxacillin activity and includes a Cetyl alcohol ------do---- 100.0 10% excess. To calculate the amount of sodium dicloxacillin Methylene chloride ------liters-- 7.575 to be used, apply the following formula: 0.825X1000 Grams coated sodium Note: This preparation must be kept at a temperature Potency of coated sodium dicloxacillinto use of 20° C. to 25 C. to prevent the waxes from precipi dicloxacillin in mcg../mg. per bottle. tating out of solution. 25 Manufacturing instructions (1) Mix all of the ingredients except the spray coated Manufacturing instructions Sodium dicloxacillin and the kaolin with approximately (1) In a suitable stainless steel container and with the one-third of the sucrose in a suitable blender. Mix for 30 aid of a mixer (e.g. a Lightnin mixer) dissolve the 30 minutes. Castorwax, beeswax, and cetyl alcohol with methylene (2) Add the blend from Step it 1 to the remainder of chloride. If necessary use steam as a heat source in order the sucrose and add the kaolin. Mix for 30 minutes. to maintain a temperature of about 25 C. and facilitate (3) Add the spray coated sodium dicloxacillin to the dissolution of the Castorwax. blend in Step #2 and mix for 30 minutes. (2) To the clear solution obtained in Step it 1, add 35 (4) Fill into 3 oz. round flint bottles. the ethylcellulose in small portions while maintaining Reconstitution: Add a sufficient volume of distilled wa agitation until a clear viscous solution is obtained. ter to make 60.0 ml. This will yield a suspension having (3) To the solution in Step #2 add the sodium di 10% over the label claim potency of 62.5 mg. per 5 ml. of cloxacillin in small portions while maintaining agitation. sodium dicloxacillin activity. Continue mixing until a milky white suspension is ob 40 tained. It must be free from lumps or small aggregates. EXAMPLE 7 (4) Pass the solution obtained in Step it 3 through three layers of cheesecloth if necessary in order to remove Spray coated ethylcellulose-Castorwax-hydrogenated pea particulate contaminants. nut oil flakes-aratex-seasame oil-sodium dicloxacillin (5) Transfer the dispersion from Step #4 into the 45 Graco pump and spray gun assembly (Monarch model). Formula Connect the pump to the 100 lbs. compressed air supply Amounts per and circulate the dispersion for at least 5 minutes by man 1000 grams ually adjusting the air pressure to 60 lbs. Sodium dicloxacillin, micronized ------grams-- 250.0 (6) Fit the Graco spray gun with tip iDLN-C1150 50 Ethylcellulose (viscosity 100 cps.) ------do---- 250.0 (.011'). Hydrogenated peanut oil flakes ------do---- 163.0 (7) Assemble the Nerco-Niro Laboratory spray drier Hydrogenated vegetable oil with lecithin (Aratex, completely with the exception of the air driven atomizing Durkee Famous Foods) ------grams-- 163.0 turbine and establish the following temperature equilib Castorwax (melting point 85°C.) ------do---- 11 1.0 : Sesame oil, U.S.P. ------do---- 63.0 Methylene chloride ------liters. 7.575 Inlet air: 115 C-120° C. Note: This preparation must be kept at a temperature Outlet air: 45 C.-50 C. of 20° C. to 25 C. to prevent the waxes from precipitat (8) Remove the porthole from the side of the spray 60 ing out of solution. drier, insert the spray gun and activate the gun main taining constant spraying. Manufacturing instructions (9) Occasionally inspect the gun for clogging, remove (1) In a suitable stainless steel container and with the and clean tip if necessary. aid of a mixer, (e.g. a Lightnin mixer) dissolve the Castor (10) Collect the product and dry in the vacuum oven Wax hydrogenated peanut oil flakes, Aratex and sesame at room temperature overnight. The methylene chloride oil with methylene chloride. If necessary use steam as a residue is less than 0.5%. heat source in order to maintain a temperature of about (11) The free flowing coated sodium dicloxacillin is 25 C. and facilitate dissolution of the Castorwax. passed through a 40 mesh screen and collected. (2) To the clear solution obtained in Step #1, add the ethylcellulose in small portions while maintaining agita EXAMPLE 6 tion until a clear viscous solution is obtained. (3) To the solution in Step #2 add the sodium diclox Spray coated sodium dicloxacillin for oral suspension, 62.5 acillin in small portions while maintaining agitation. Con mg./5 ml. (ethylcellulose-beeswax-Castorwax-cetyl al tinue mixing until a milky white suspension is obtained. cohol coating). It must be free from lumps or small aggregates. 3,549,746 O (4) Pass the solution obtained in Step i3 through three EXAMPLE 9 layers of cheesecloth, if necessary, to remove particulate contaminants. Spray coated ethylcellulose-spermaceti-Castorwax-sodium (5) Transfer the dispersion from Step #4 into the dicloxacillin Graco pump and spray gun assembly (Monarch model). Connect the pump to the 100 lbs. compressed air supply 5 Formula and circulate the dispersion for at least 5 minutes by man Amounts for ually adjusting the air pressure to 60 lbs. 1000 grams (6) Fit the Graco spray gun with tip iDLN-C1150 Sodium dicloxacillin, micronized ------grams. 250.0 (.011'). 10 Ethylcellulose (viscosity 100 cps.) ------do---- 250.0 (7) Assemble the Nerco-Niro Laboratory spray drier Spermaceti wax ------do---- 333.0 completely with the exception of the air driven atomizing Castorwax (melting point 85 C.) ------do---- 167.0 turbine and establish the following temperature equilib Methylene chloride ------liters.- 15.0 Note: This preparation must be prepared and kept at Inlet air: 115 C-120° C. 5 a temperature of 20-25 C. in order to maintain solu Outlet air: 45 C.-50° C. bility of the Castorwax. Lower temperatures will innevita (8) Remove the porthole from the side of the spray bly lead to wax precipitation. The use of steam is rec drier, insert the spray gun and activate the gun maintain ommended as a source of heat. ing constant spraying. 20 Manufacturing instructions (9) Occasionally inspect the gun for clogging, remove and clean tip if necessary. (1) Dissolve the spermaceti wax and Castorwax in 15 (10) Collect the product and dry in the vacuum oven liters of methylene chloride. The operation is carried out at room temperature overnight. The methylene chloride in a stainless steel container with the aid of a mixer, residue is less than 0.5%. (e.g. a Lightnin mixer). Maintain the temperature at (11) The free flowing coated sodium dicloxacillin prod about 20-25 C. with the aid of steam if necessary. uct is passed through a 40 mesh screen and collected. (2) To the clear solution obtained in Step it 1, add the ethylcellulose in small portions while maintaining EXAMPLE 8 agitation. Stir until a clear and relatively viscous solution 30 is obtained. Spray coated sodium dicloxacillin for oral suspension, (3) The sodium dicloxacillin is then added in small 62.5 mg. 5 ml. (ethylcellulose-Castorwax-Aratex-ses portions while maintaining agitation. A milky white sus ame oil-hydrogenated peanut oil coating pension will result. The dispersion must be free from small lumps or agglomerates. Formula Per 60 ml. 35 (4) Strain the solution obtained in Step #3 through Sodium dicloxacillin (spray coated three layers of cheesecloth if necessary to remove any par ethylcellulose-Castorwax - Aratex ticulate contaminants. tex-sesame oil-hydrogenated pea (5) The Nerco-Niro Laboratory Model spray drier is nut oil from Example 7) ------10.825 gram (di readied as follows for the following conditions: cloxacillin activ 40 Note: Assemble completely before starting except for ity), 3.7 g. the atomizer. Sodium cyclamate ------2.400 grams. (a) Turn on the electric heater to setting #2 or 3 Sodium Saccharin ------0.400 gram. until the inlet air gauge reads around 130° C. Sodium citrate, anhydrous ------0.420 gram. (b) When equilibrium is reached: Sodium benzoate ------0.060 gram. Sodium chloride ------1.200 grams. The inlet air gauge will read-115-120° C. Gum tragacanth ------0.425 gram. The outlet air gauge will read-50°-55° C. Kaolin ------6.000 grams. (c) Install the turbine atomizer in its proper position Sucrose, 30 mesh ------25.000 grams. over a Teflon gasket and feed compressed air until the Dye ------0.500 gram. 50 atomizer gauge reads 6 kg./cm2. At this point maximum Flavors ------0.930 gram. compressed air pressure is in use (90-100 lbs.) and the 1. This figure represents dicloxacillin activity and includes turbine is turning at a rate of 40,000 r.p.m. Allow 5 min a 10% excess. To calculate the amount of sodium dicloxacil utes for equilibrium in the chamber before liquid feeding in to be used, apply the following formula : is commenced. (d) Start liquid feed to the turbine from a 2 liter sepa 0.825X1000 Grams coated sodium ratory funnel connected to the turbine by a short piece Potency of coated sodium dicloxacillin to use of Teflon tubing. Feed at a rate of 60 to 80 ml. per min dicloxacillin in mcg../mg. per bottle. ute. (e) Monitor the operation to maintain the following 60 drying conditions throughout the entire operation: Manufacturing instructions Inlet air: 115-120° C. (1) Mix all of the ingredients except the spray coated Outlet air: 60-70° C. sodium dicloxacillin and the kaolin with approximately (f) Stop the atomizer and turn the electric heater to one-third of the sucrose in a suitable blender. Mix for 30 position M (exhaust fan) allow 5 minutes in this position minutes. before lifting cover. (2) Add the blend from Step #1 to the remainder of (g) Lift cover with the aid of the hydraulic lift and the sucrose and add the kaolin. Mix for 30 minutes. collect product from the walls. The product is not ex (3) Add the spray coated sodium dicloxacillin to the pected to stick to the walls of the chamber other than by blend in Step it 2 and mix for 30 minutes. 70 electrostatic forces. (4) Fill into 3 oz. round flint bottles. (h) Dry product in vacuum oven overnight at room Reconstitution: Add a sufficient volume of distilled temperature. The methylene chloride residue is less than water to make 60.0 ml. This will yield a suspension hav 0.5%. ing 10% over the label claim potency of 62.5 mg. per 5 (i) The free flowing coated sodium dicloxacillin prod ml. of sodium dicloxacillin activity. 75 uct is passed through a 40 mesh screen and collected. 3,549,746 12 EXAMPLE 10 Five ml. of each of the suspensions were administered Spray coated sodium dicloxacillin for oral suspension, orally to each of twelve subjects, and the blood levels 62.5 mg./5 ml. (ethylcellulose-spermaceti-Castorwax attained thereby were measured after periods of /2, 1, 2, coating) 3, and 4 hours after administration. It is obvious by inspection of the tables that the sus Formula Per 60 ml. pensions employing coated dicloxacillin gave blood levels Sodium dicloxacillin (spray coated comparable to those attained with the suspensions em ethylcellulose - spermaceti - Castor ploying uncoated dicloxacillin. wax from Example 9) ------0.825 gram (dicloxacillin EXAMPLE 12 activity), 3.7 g. O According to the procedure of Example 2, eight oral Sodium cyclamate ------2.400 grams. suspensions are prepared in which dicloxacillin is re Sodium Saccharin ------0.400 gram. placed on an activity per 5 ml. basis, with 62.5 mg. Sodium citrate, anhydrous ------0.420 gram. ampicillin, 62.5 mg. hetacillin, 62.5 mg. cloxacillin, 62.5 Sodium benzoate ------0.060 gram. mg. flucloxacillin, 62.5 mg. nafcillin, a mixture contain Sodium chloride ------1.200 grams. ing 125 mg. of amplicillin and 62.5 mg. of dicloxacillin, Gum tragacanth ------0.425 gram. a mixture containing 125 mg. of hetacillin and 62.5 mg. Kaolin ------6.000 grams. of dicloxacillin, a mixture containing 125 mg. of ampi Sucrose, 30 mesh ------25.000 grams. cillin and 62.5 mg. of cloxacillin, and a mixture contain Dye ------0.500 gram. ing 125 mg. of hetacillin and 62.5 mg. of cloxacillin, re Flavors ------0.930 gram. 20 spectively, which have been previously coated as de This figure represents dicloxacillin activity and includes scribed in Example 1 above. a 10% excess. To calculate the amount of sodium dicloxacil lin to be used, apply the following formula : EXAMPLE 13 Spray coated ethylcellulose-spermaceti-Castorwax O.S25X1000 Grams coated sodium 25 ampicillin trihydrate Potency of coated sodium dicloxacillin to use Amounts for dicloxacillin in meg./mg, per bottle. Formula: 1000 grams Manufacturing instructions Ampicillin trihydrate, micronized --grams. 900.0 (1) Mix all of the ingredients except the spray coated Ethylcellulose (viscosity 100 cps.) --do. 33.3 Sodium dicloxacillin and the kaolin with approximately Spermaceti Wax ------do---. 44.5 one-third of the sucrose in a suitable blender. Mix for Castorwax (melting point 85 C.) ---do---- 22.2 30 minutes. Methylene chloride ------liters- 9.0 (2) Add the blend from Step #1 to the remainder of Manufacturing instructions the sucrose and add the kaolin. Mix for 30 minutes. Dissolve the ethylcellulose, spermaceti wax and Castor (3) Add the spray coated sodium dicloxacillin to the wax in 9.0 liters of methylene chloride at room tempera blend in Step #2 and mix for 30 minutes. ture. Then add and disperse the micronized ampicillin (4) Fill into 3 oz. round flint bottles. trihydrate. Mix until uniform and strain through three Reconstitution: Add a sufficient volume of distilled layers of cheesecloth to remove any particulate contami water to make 60.0 ml. This will yield a suspension hav nates. Spray dry (apparatus and method described in ing 10% over the label claim potency of 62.5 mg. per 40 Example 9) using air inlet temperature of 125°-135° C. 5 ml. of sodium dicloxacillin activity. and outlet temperature of 50-70° C. The product coated ampicillin trihydrate is spread on trays and dried over EXAMPLE 11 night at room temperature and then passed through a A comparison was made of the blood levels obtained 40 mesh screen and collected. by oral administration of suspensions containing coated EXAMPLE 14.-SPRAY COATED AMPICLLIN TRI dicloxacillin with the blood levels obtained by oral ad HYDRATE FOR ORAL SUSPENSION 125 mg/ETHYL ministration of like Suspensions containing uncoated di CELLULOSE-SPERMACETI-CASTORWAX COATING) cloxacillin. A crossover study was used to determine the blood levels of the penicillin in human subjects. The 50 results of the study are recorded in Tables I and II below: Formula, i 1.575 gram TABLE Ampicillin trihydrate, gn------2.07 2.07 20.1 Suorose, gm------28.0 28.0 25.0 Averagepatients, blood ng.fml. level for 12 Sodium cyclamate, gm- 2.10 2.10 2.2 Sodium benzoate, gm------0.06 .06 0.06 Colloidal magnesium aluminum silicate, gm 3--- 6.0 7.0 8.0 Hours after administration 55 Citric acid anhydrous, gn------0.20 0.23 0.263 Dye, gm------1.50 50 1.50 as 1. 2 3 4. Flavors, gm------0.94 1.53 1.53 Suspension: Reconstitution water volume, ml 34 33 34 Control------2.42 3.33 2. 15 1.05 0.45 1 This figure represents ampicillin trihydrate activity and includes a Example 2------3.72 3.04 2,82. 1.57 0.82 5% excess. To calculate the amount of amplicillin trihydrate to be used, 60 apply the following formula: 1.575X1000 TABLE II ------Grams coated amplicillin Potency of coated amplicillin trihydrate to use per Average blood level for 12 trihydrate in mcgfring. bottle. patients, mg.fml. s Spray coated Ethylcellulose-Spermaceti, CastorWax from Example 13. Hours 3 Weegum F, Vanderbilt Company Inc. 3a l 2 3. 4. NOTE.-Manufacturing instructions: (1) Mix all of the ingredients except the spray coated Suspension: ampicillin trihydrate and the colloidal magnesium alu Control------3.28, 3.71 2.23 0.95 0.45 minum silicate with approximately one-third of the su Example 4--- -- 2.84 3.53. 3. 11 1.99 0.98 crose in a suitable blender. Mix for 80 minutes. Example 6- 2.88 3.75 2.50 I. 23 0.71 (2) Add the blend from Step it to the remainder of the Example 8------2.47 3,74 2.63 1. 41 0.83 sucrose and add the colloidal magnesium aluminum sili O cate. Mix for 30 minutes. (3) Add the spray coated amplicillin trihydrate to the For purposes of comparison the control suspension was blend in Step #2 and mix for 30 minutes. (4) Eill into 3 oz. flint bottles. prepared according to the procedure of Example 2, how Reconstitution : Add a sufficient volume of distilled water to make 60.0 ml. This will yield a suspension having ever uncoated dicloxacillin was used in place of coated 5% over the label claim potency of 125 mg. per 5 ml, of dicloxacillin. 75 amplicillin activity. 3,549,746 13 14 EXAMPLE 15 cloxacillin, in a mixture containing 125 mg. of hetacillin According to the procedure of Example 14 an oral and 62.5 mg. of dicloxacillin, a mixture containing 125 suspension is prepared in which amplicillin trihydrate is mg. of amplicillin and 62.5 mg. of cloxacillin, and a mix replaced, on an activity per 5 ml. basis, with 125 mg. of ture containing 125 mg. of hetacillin and 62.5 mg. of anhydrous amplicillin which has been previously coated cloxacillin, respectively, which have been previously as described in Example 13. coated as described in Example 1 above. EXAMPLE 16 EXAMPLE 21 According to the procedure of Example 18, five lots of Sodium dicloxacillin monohydrate capsules tablets are produced in which dicloxacillin is replaced, Formula O on a per tablet basis, with 125 mg. ampicillin, 125 mg. Per capsule hetacillin, 125 mg. oxacillin, 125 mg. cloxacillin, 125 mg. Sodium dicloxacillin (ethylcellu- 62.5 mg., 125 mg. or flucloxacillin, 125 mg. of nafcillin, a mixture containing lose - spermaceti spray coated 250 mg. activity. 125 mg. of amplicillin and 62.5 mg. of dicloxacillin, a mix from Example 1). ture containing 125 mg. of hetacillin and 62.5 mg. of Anhydrous lactose, U.S.P. ------Q.s. 5 dicloxacillin, a mixture containing 125 mg. of ampicillin Magnesium stearate, U.S.P. ----- Q.S. and 62.5 mg. of cloxacillin, and a mixture containing 125 Manufacturing procedure mg. of hetacillin and 62.5 mg. of cloxacillin, respectively, which have been previously coated as described in Ex (1) Blend the magnesium sterate, the anhydrous lactose 20 ample 1 above. and the spray coated sodium dicloxacillin and fill into a In the present invention and particularly in the exam suitable capsule size. ples, hetacillin free acid is taken as the standard with an EXAMPLE 17 activity of 1000 mcg../mgm. and when other salts are used, the weight taken is that which gives an equivalent Sodium dicloxacillin monohydrate tablets amount of activity, i.e., 1096 mgms. of potassium heta Formula cillin are equivalent in activity to 1000 mgms. of hetacil Per tablet lin free acid. The relationship is stoichiometric. Sodium dicloxacillin (ethylcellu 62.5 mg., 125 mg. or In the case of ampicillin the standard with an activity lose, spermaceti spray coated 250 mg. activity. of 1000 mcg../mgm. is anhydrous ampicillin and thus from Example 1). 30 ampicillin trihydrate has a potency of 865 mcg./mgm. Carbowax 6000, micropulverized - 41.5 to 100 mg. In the case of dicloxacillin, the standard is the free acid Magnesium stearate, U.S.P. ----- A sufficient quantity. with an activity of 1000mcg../mgm. and thus the sodium Manufacturing procedure salt is 920 mcg../mgm. In the actual formulations use is often made as is (1) Blend the sodium dicloxacillin, the Carbowax and 35 customary in this field of an overfill, e.g., of ten percent, mangesium stearate in a suitable mixer. Tablet by direct of each active ingredient as compared to labelled potency. compression to a suitable hardness. While this invention has been described in terms of its EXAMPLE 18 preferred embodiment, those skilled in the art will appre ciate that modifications can be made without departing Sodium dicloxacillin monohydrate tablets 40 from the spirit and scope of this invention. Formula We claim: Per tablet 1. A pharmaceutical composition in unit dosage form Sodium dicloxacillin (ethylcellu- 62.5 mg., 125 mg. or which comprises coated particles having a particle size lose - spermaceti spray coated 250 mg. activity. not larger than 40 mesh of a micronized penicillin se from Example 1). 45 lected from the group consisting of amplicillin, hetacillin, Calcium carbonate starch granules, 200 mg. to 500 mg. nafcillin, oxacillin, cloxacillin, dicloxacillin, and flucloxa 60 mesh. cillin and mixtures thereof and a pharmaceutical carrier; Sucrose, U.S.P. powdered ------100 mg. to 250 mg. wherein said coated particles comprise from about 9 parts Magnesium stearate, U.S.P. ----- Q.S. as required. by weight of penicillin per part by weight of coating to 50 about 7 parts by weight of coating per part by weight of Manufacturing procedure penicillin and said coating comprises ethylcellulose and (1) Blend all the ingredients together in a suitable from about 1 to about 3 parts by weight of spermaceti mixer. Tablet by direct compression to a suitable hard wax per part by weight of ethylcellulose. CSS. 2. The composition of claim 1 wherein said penicillin EXAMPLE 19 55 is dicloxacillin. According to the procedure of Example 16, five lots 3. The composition of claim 1 wherein said penicillin of capsules are produced in which dicloxacillin is re is dicloxacillin and said coated particles comprise about 3 placed, on a per capsule basis, with 125 mg. amplicillin, parts by weight of coating per part by weight of dicloxa 125 mg. hetacillin, 125 mg. oxacillin, 125 mg. cloxocillin, cillin and said coating comprises about 2 parts by weight 125 mg. flucloxacillin, 125 mg. of nafcillin, a mixture con 60 of spermaceti wax per part by weight of ethylcellulose. taining 125 mg. of amplicillin and 62.5 mg. of dicloxa 4. The composition of claim 1 where said penicillin cillin, a mixture containing 125 mg. of hetacillin and is dicloxacillin and said coated particles comprise about 62.5 mg. of dicloxacillin, a mixture containing 125 mg. 3 parts by weight of coating per part by weight of dicloxa of ampicillin and 62.5 mg. of cloxacillin, and a mixture cillin and said coating comprises about 1.7 parts by containing 125 mg. of hetacillin and 62.5 mg. of cloxa 65 weight of spermaceti wax and 0.3 part by weight of hy cillin, respectively, which have been previously coated as drogenated castor oil per part by weight of ethylcellulose. described in Example 1 above. 5. The composition of claim 4 comprising at least about 50 mgm. of said penicillin. EXAMPLE 20 6. The composition of claim 1 wherein said penicillin According to the procedure of Example 17, five lots 70 is amplicillin. of tablets are produced in which dicloxacillin is replaced, 7. The composition of claim 1 wherein said penicillin on a per tablet basis, with 125 mg. amplicillin, 125 mg. is ampicillin and said coated particles comprise about 9 hetacillin, 125 mg. oxacillin, 125 mg. cloxacillin, 125 parts by weight of amplicillin per part by weight of coat mg. flucloxacillin, and 125 mg. of nafcillin, a mixture ing and said coating comprises about 2 parts by weight containing 125 mg. of ampicillin and 62.5 mg. of di of spermaceti wax per part by weight of ethylcellulose. 3,549,746 5 6 8. The composition of claim 1 wherein said penicillin recovering the coated penicillin particles produced thereby is amplicillin and said coated particles comprise about 9 having a particle size not larger than 40 mesh; said coated parts by weight of amplicillin per part by weight of coating particles having improved taste and the penicillin con and said coating comprises about 1.3 parts by weight of tained therein being efficiently absorbed from the human spermaceti wax and 0.7 part by weight of hydrogenated gastrointestinal tract upon oral administration of a com castor oil per part by weight of ethylcellulose. 5 position comprising said coated penicillin particles and a 9. The composition of claim 8 comprising at least pharmaceutical carrier. about 50 mgm. of said penicillin. 10. A method of coating a penicillin selected from the References Cited group consisting of amplicillin, hetacillin, nafcillin, Oxa O UNITED STATES PATENTS cillin, cloxacillin, dicloxacillin and flucloxacillin and mix tures thereof which comprises suspending micronized par 2,487,336 11/1949 Hinds ------424-38 ticles of the penicillin in a solution comprising ethyl 2,805,977 9/1957 Robinson et al. -----. 424-35 cellulose and from about 1 to about 3 parts by weight of 2,902,407 9/1959 Gross et al. ------424-271 spermaceti wax per part by weight of ethylcellulose in a 2,921,883 1/1960 Reese et al. ------424-35 nonreactive volatile organic solvent to produce a suspen 2,980,589 4/1961. De Grunigen ------424-271 sion, wherein said penicillin is present in the proportion of 3,247,065 4/1966 Koff------424-35 from about 9 parts by weight of penicillin per part by weight of ethylcellulose and spermaceti wax to about 7 STANLEY J. FRIEDMAN, Primary Examiner parts by weight of ethylcellulose and spermaceti wax per 20 U.S. C. X.R. part by weight of penicillin, spraying said Suspension into 424-38, 155, 271 a heated nonreactive gaseous medium at a temperature of about 240 to 260 F. to produce coated particles and