US3081233A - Enteric-coated pilules - Google Patents
Enteric-coated pilules Download PDFInfo
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- US3081233A US3081233A US47951A US4795160A US3081233A US 3081233 A US3081233 A US 3081233A US 47951 A US47951 A US 47951A US 4795160 A US4795160 A US 4795160A US 3081233 A US3081233 A US 3081233A
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- pilules
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- erythromycin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
- A61K9/5078—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings with drug-free core
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- This invention relates to new dosage forms for medicinals, and more particularly relates to pharmaceutical preparations containing enteric pilules measuring not more than about Oil inch in diameter, the coating being a single, non-toxic, acidic, enteric film-forming material.
- an object of the present invention to provide a new enteric dosage form which is well adapted to oral therapeutic use. Another object is to provide such a dosage form which is innocuous to the taste and is especially well-adapted to pediatric use. Another 'object is to provide such dosage forms which :are not disintegrated in the stomach, and yet are readily available for absorption in the upper intestinal tract. Still another object is to provide such a dosage form which gives better therapeutic results. Still another object is to provide such a dosage form for medicinals absorbed into the blood which gives appreciably faster, higher and/or more consistent bloodlevels than dosage forms available to the prior art. "Still another object is the provision of a novel process for the preparation of such a dosage form. Other objects will be apparent to those skilled in the art to which this invention pertains.
- an oral pharmaceutical preparation containing uniform, spherical, enteric pilules measuring not more than about 0.1 inch in diameter comprising '(a) a medicinal agent and (b) :a coating of a single enteric film-forming material.
- the pilutes will not disintegrate in the mouth and can be sugar coated so that taste of the medicinal is completely masked.
- the medicinal in this form will not be rapidly destroyed in the stomach, will not cause nausea or other irritation, and can be given irrespective of meals. It is particularly well adapted to pediatric use since children may take it .at any suitable time.
- enteric pilules can be formulated into a variety of finished pharmaceutical forms, for example, packets, twopiece hard gelatin capsules which can be sealed, one-piece sofit gelatin capsules, liquid suspensions, and the like.
- the pilules are prepared by rolling the desired medicinal on moistened pill starters until small pills (pilules) are produced.
- the pilules are dried and subsequently coated with the enteric coating material.
- a large number of medicinal agents can be prepared in the dosage forms of the present invention. Although the reasons for enteric coating these materials are different, the advantages inherent in the dosage form of the present invention are the same for each of these materials, i.e., quicker, better land/or more consistent therapeutic results are obtained in the dosage form of the present invention. For medicinals, such as erythromycin and penicillin, which are absorbed into the blood stream these advantages show up as quicker, higher and/or more consistent blood levels.
- Anthelmintics-santonin, piperazine citrate, etc. to improve taste, reduce irritation in mouth and stomach.
- Hormones-adrenocorticosteroids for example, 6a-methylprednisolone, hydrocortisone, and 9a-fiuoro- 16a-hydroxyprednisolone; androgenic steroids, for example, methyltestosterone, and 9a-fluoro-llp,l7fi-dihydroxy-17a-methyl-4-androstene-3-one; estrogenic steroids,
- progestational steroids for example, 17a-hydroxyprogesterone acetate, 6ct-methyl-17a-hydroxyprogesterone 17-acetate, and l7a-ethinyl-19-nortestosterone
- Psycic energizer agents for example, indole, 3-(2-aminopropyl)-, acetate and indole, 3-(2-aminobutyl)-, acetate, to attain prolonged absorption.
- enteric materials are suitable for the novel dosage forms of the present invention.
- enteric materials serve the purpose of resisting disintegration of the coating until the pilules pass through the stomach into the intestine.
- enteric materials and mixtures containing such materials include keratin, formalized gelatin, calcium alginate, shellac and like naturally occurring resinous substances, cellulose acetate phthalate, starch acetate phthalate, amylose acetate phthalate, partially hydrolyzed styrene-maleic anhydride copolymer, styrene-maleic acid copolymer, polyvinyl acetate phthalate, and polyvinyl hydrogenphthalate; shellacwool fat, shellac-caster oil, shellac-cetyl alcohol, shellacammonia, shellac-ammonia-alcohol; and the like.
- the size of the finished pilules is very important.
- the size of the pill starters depends upon the finished size of the pilules to be produced and the amount of the other ingredients to be used therein.
- the amount of active material and the thickness of the enteric coat is adjusted to obtain a pilule not exceeding about 0.1 inch in diameter. It is preferred that the finished pilule range in size between about 0.04 and about 0.085 inch in diameter.
- the finished pilule size is a critical feature of the present invention.
- an unweighed quantity of bolted sucrose (30 40 mesh) is placed in a revolving pill tub and moistened with a spray of deionized or distilled water until uniformly moistened. Uniformity in size of the bolted sucrose is more important at this stage than is the relative size of the sucrose granules.
- a small amount of a homogeneous mixture of talc, starch and sucrose (20:5:1) is dusted on the moistened sucrose. The tale, starch, sucrose mixture rolls onto the moistened sucrose.
- the contents of the pill tub are alternately water-sprayed and powder-dusted until spherical masses, called pill starters, are produced.
- the smaller spheres which are separated from the larger spheres by screening during processing, are returned to the pill tub and brought up to proper size by the above described method. Those spheres which are out of shape at this point are preferably discarded. Only round, smooth starters are desirable.
- a sufficient number of the spheres (or pill starters) of the proper size are placed in a revolving pill tub and sprayed with distilled or deionized Water until the pilules are uniformly moistened.
- a homogeneous mixture of the desired medicinal (e.g., erythromycin) three parts, talc 7.5 parts, starch two parts and sucrose one part, is dusted on the moistened pill starters. Again the water spraying and powder dusting are repeated alternately until the pilules are of the proper size. The pilules are air dried and then assayed for content of the active material.
- the pilules After the pilules have dried and the content of medicinal has been determined, the pilules are given several coats of an enteric material, using tale for dusting.
- the finished pilules are built up from an inert core by adding 1) a layer containing a medicinal agent, and (2) an outer layer containing a single, non-toxic, acidic, enteric film-forming material.
- the finished enteric coated pilules must resist artificial gastric juice (pH 1.2) for at least sixty minutes.
- the coatings designed to make the medicament rapidly available should disintegrate within sixty minutes in pH 6.8 buffer solution (citrate phosphate buffer) at 37 degrees Centigrade when subject to controlled and constant agitation in the buffer solutions.
- the coatings designed to provide prolonged availability of the medicament should disintegrate over a period of from about one to about seven hours in buffers from pH about 3.0 to about 8.0.
- enteric coated pilules can be sugar coated if desired and are now ready for therapeutic use. They may be mixed with various foods and their size is such that the average person taking the'pilules will be unaware of their presence in the food. Therapeutic doses are generally prepared in packets and capsules to better control the amount of each dose. Pilules containing one active material may also be mixed with other pilules containing other active materials for combined treatment with two or more active materials.
- the dosage form of the present invention be limited to spherical pilules from the standpoint of therapeutic results, it is desirable for other reasons. Appearance is better when the individual units are uniform.
- the dosage of active ingredient is easier to control when the units are uniform.
- the thickness of the enteric coat and the uniformity of the enteric coat are more difficult to control for irregularly shaped solids.
- the size of the units is easier to control if prepared in a uniform manner, and spherical units are easier to administer and less irritating.
- EXAMPLE 1 Erythromycin Pilules of the pill tub are alternately water sprayed and powder dusted until spherical masses, called pill starters, having a diameter between 0.040 and 0.050 inch, are produced.
- the smaller spheres are separated from the larger ones by screening during processing. They are returned to the pill tub and brought up to the proper size by the above described method. Those spheres which are out of shape at this point are discarded. Only round, smooth starters are used to form pilules.
- the pill starters are placed in a revolving pill tub and sprayed with deionized water until the pilules are uniformly moistened.
- a homogeneous mixture of erythromycin three parts, talc 7.5 parts, starch two parts and sucrose one part, is dusted on the moistened pill starters.
- the water spraying and powder dusting are repeated until the pilules range in size from 0.065 to 0.071 inch in diameter.
- the pilules are air dried and assayed for erythromycin content.
- the pilules are given several coats of cellulose acetate phthalate described in U.S. Patent 2,196,768 in an absolute alcohol-acetone solution having one to one ratio using tale for dusting. This procedure is continued until round and smooth pilules ranging in size from 0.065 to 0.085 inch in diameter are obtained.
- the coating of the pilule should resist artificial gastric juice (pH 1.2) for at least sixty minutes and should disintegrate within sixty minutes in pH 6.8 butler solution (citnate phosphate buffer) at 37 degrees centigrade when subjected to controlled and constant agitation in the butler solutions.
- the pilules are packaged in groups of 100, each packet supplying one therapeutic dose of about fifty milligrams (allowing for losses in manufacture and storage).
- EXAMPLE 2 Salicylate Pilules Following the procedure of Example 1 pilules containing sodium salicylate as the active ingredient and coated with ammoniated shellac can also be prepared by substituting sodium salicylate for erythromycin and ammoniated shellac for cellulose acetate phthalate.
- EXAMPLE 3 Ferrous Gluconate Pilules One million pilules containing ferrous gluconate as the ingredient are prepared from the following types and amounts of materials.
- Ferrous gluconate N.F., 3 lbs. 9 oz. 63 grs. Talc, U.S.P., 4 lbs. 8 oz.
- Cane sugar powder U.S.P., 10 oz. 125 grs.
- Round, smooth pill starters are prepared as described in Example 1.
- One million of these pill starters are placed in a revolving pill tub and sprayed with deionized water until the pilules are uniformly moistened.
- a homogeneous mixture of ferrous gluconate 6.25 parts, talc seven parts, starch two parts and cane sugar one pant is dusted on the moistened pill starters.
- the Water spraying and powder dusting are repeated until the pilules range in size from 0.065 to 0.075 inch in diameter.
- the pilules are air dried and assayed for ferrous gluconate content.
- the pilules are replaced in a pill tub and given three coats of a thirty percent shellac in ethanol solution using talc for dusting.
- the pilules are then dried with a blast of hot air and two coats of a solution of gelatin, sucrose and water are applied with talc for dusting.
- a sufiicient number of coats of the gelatin-sucrose solution are applied using a mixture of precipitated calcium carbonate, talc and acacia, for dusting until 100 pilules laid end to end measure three and one-half inches.
- Serum samples were assayed for erythromycin by a modification of the Rammelkamp (serial dilution) method employing Streptococcus hemolyticus as the test organism.
- the results are presented in the following tables (I through VI) and are given in terms of micrograms of erythromycin per milliliter of serum. Essentially, the tables are arranged and numbered in the same order as the dosage terms listed immediate, higher and more consistent blood levels.
- the sodium salicylate was administered at the level of 113 mg./ kg. of body weight.
- Four five grain tablets contained about 1300 milligrams of sodium salicylate while some 700 odd pilules were used to give 1300 milligrams of the drug. These two drug preparations gave similar disintegration times in vitro.
- Table VI gives striking evidence of quicker,
- the dosage form of the present invention is believed to be especially adaptable to pediatric use, it was tested on a group of eighteen children ranging in age from four months to fourteen years to test for patient acceptance.
- various foods used as vehicles were pureed peaches, carrots, pears, pablum, apple sauce, beef, potatoes, rice, green beans, tomatoes, ice cream, soup, chocolate pudding, juice, and cereal.
- acceptance was good, and the studies show that the pilules should be mixed with food that does not require mastication, such as pureed fruits, pudding, juice and the like.
- the enteric coated erythromycin pilules were used to treat five children under two years of age at a dose of five milligrams per pound.
- the pilules were administered on a dry spoon or mixed with pudding and were taken without objection by the children.
- Table VII summarizes the blood levels obtained in micrograms of erythromycin per milliliter of blood.
- Tables VIII and IX illustrate the superiority of the pilules over a comparable suspension when administered to children.
- erythromycin (about 2.5 mg./lb.). Time: V2 hour before breakfast] Blood level at intervals, hours Preparation Erythroruycin enteric pilules with triple sulfa pilules Average range .458 .263 182 .114 .079 Ratio (0) 1 0. 81 0-. 440 0-. 480 .072.236 .046-.144 8/9 8/9 8/9 9/9 9/9 Enteric coated erythromyein tablets laminated with Average range .3 49 .121 .063 .054 triple Sums, Ratio 0 1 0-1. 34 0-. 654 .oso-. 22 0-. 0-.
- EXAMPLE 6 eral oil is added. It is preferred to use 1 1b. 8 ozs. 297 Steroid Pilules grs. of di-n-di butylphthalate as plastioizer in the coating 50,000,000 enteric coated pilules containing 6a-methyl 75 solution.
- the ingredients are uniformly mixed using a No. 12 wire in the mixer.
- the pill starters are sprayed in a revolving pill tub with deionized water until uniformly moistened.
- the medicinal agent mixture is dusted on the moistened starters.
- the spraying and dusting are repeated until the average diameter of the pilules is from 0.048-0.049 in.
- the pilules are air dried and assayed tor steroid content.
- the assayed pilules are coated with the coating solution using the magnesium stearate-talc mixture as dusting powder, until the average diameter is from 0.0510.052 in.
- the coated pilules are assayed for steroid content.
- coated pilules are encapsulated into two-piece hard gelatin capsules each containing 4 mgs. of 6u-methylprednisolone in the form of 140 enteric-coated pilules.
- the oral administration to humans of one to two capsules daily provides beneficial results with lowered incidence of side eifects in rheumatoid arthritis.
- Advantageous, consistent blood levels of 17-OH corticosteroids are obtained in the oral treatment of addisonian disease.
- the starters are sprayed until uniformly wet with a 1% aqueous solution of the polyoxyethylene sorbitan monolaurate.
- a homogeneous mixture of the antimony potassium bitartrate, the cane sugar, starch and talc is dusted on the wet starters. The spraying and dusting are repeated until the average diameter of 600 pilules is about 0.048 in. The pilues are air dried and assayed for antimony potassium bit-artrate content.
- the pilules are given several coats of hydrolysed styrene-maleic anhydride copolymer in an anhydrous ethanol solution containing mineral oil and di-nbuty-l phthalate, using the magnesium stearate-talc mixture as a dusting powder. This procedure is continued until uniform spherical pilules with an average diameter of about 0.055 in. are obtained. Beneficial results are obtained in the oral treatment of dermal leishmaniasis at a daily dose of 3 to 4 capsules.
- the pilules are encapsulated into two-piece hard gelatin capsules each containing 22 mgs. of the medicinal agent in the form of 160 pilules.
- EXAMPLE 8 Psychic Energizer Pilules Following the procedure of Example 6, 1,000,000 enteric coated pilules are prepared from the following types and amounts of materials.
- Pill starters prepared as in Example 1 (average diameter 0.042 in.) 1,000,000
- Styrene-maleic acid copolymer gms 700 Ethanol anhydrous, denatured cc 4670 Di-n-butylphthalate gms 84 White mineral oil, viscosity 180 gms 140 Dusting powder:
- the average diameter of the enteric coated pilules is 0.052 in. pilules contain 5 mgs. of the medicinal agent.
- the oral administration to male humans of one capsule daily provides beneficial results in the treatment of androgen deficiencies.
- An oral pharmaceutical preparation containing a plurality of enteric-coated pilules each of which measures not more than about 0.1 inch in diameter, is spherical, and has a uniform thickness of enteric coating and comprises (a) a medicinal agent and (b) a coating of a single, non-toxic, acidic, enteric film-forming material surrounding said agent, the plurality providing a unit dose of the medicinal agent.
- a process for preparing a plurality of spherical enteric-coated pilules which comprises preparing uniform spherical pill starters, applying thereto a coating of a medicinal agent which is advantageously administered orally in enteric-coated form and applying a coating of a single, non-toxic, enteric film-forming material, each step being so carried out as to provide pilules measuring not more than about 0.1 inch in diameter.
- non-toxic, acidic, enteric film-foaming material surrounding said agent the plurality providing a unit dose of the medicinal agent.
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Description
United States Patent O 3,081,233 ENTERIC-COATED PILULES Walter F. Enz, Kalamazoo Township, Kalamazoo County, and Thurlow E. King, Pavilion Township, Kalamazoo County, Mich., assignors to The Upjohn Company, Kalamazoo, Mich., a corporation of Delaware No Drawing. Filed Aug. 8, 1960, Ser. No. 47,951 17 Claims. (Cl. 167-82) This invention relates to new dosage forms for medicinals, and more particularly relates to pharmaceutical preparations containing enteric pilules measuring not more than about Oil inch in diameter, the coating being a single, non-toxic, acidic, enteric film-forming material.
Many medicinals are most satisiactorily administered in an enteric dosage form. However, many difliculties have arisen in the attempt to produce an enteric dosage form which ideally performs its function. Many enteric dosage forms will partially disintegrate in the stomach. Some enteric dosage forms have been known to pass completely through the gastrointestinal tract without disintegrating at all. Such enteric medicinals are erratic and unreliable. This difliculty is magnified in the case of medicinals taken at or near mealtime. The slower passage of the medicinal through th stomach when taken during this period generally has an adverse effect upon its absorption into the human system. Moreover, any enteric dosage form, since it does not disintegrate until reaching the intestine, necessarily involves a delay before the medicinal ingredient begins to take effect.
It is therefore :an object of the present invention to provide a new enteric dosage form which is well adapted to oral therapeutic use. Another object is to provide such a dosage form which is innocuous to the taste and is especially well-adapted to pediatric use. Another 'object is to provide such dosage forms which :are not disintegrated in the stomach, and yet are readily available for absorption in the upper intestinal tract. Still another object is to provide such a dosage form which gives better therapeutic results. Still another object is to provide such a dosage form for medicinals absorbed into the blood which gives appreciably faster, higher and/or more consistent bloodlevels than dosage forms available to the prior art. "Still another object is the provision of a novel process for the preparation of such a dosage form. Other objects will be apparent to those skilled in the art to which this invention pertains.
The foregoing and additional objects have been accomplished by the provision of an oral pharmaceutical preparation containing uniform, spherical, enteric pilules measuring not more than about 0.1 inch in diameter comprising '(a) a medicinal agent and (b) :a coating of a single enteric film-forming material. The pilutes will not disintegrate in the mouth and can be sugar coated so that taste of the medicinal is completely masked. Moreover, the medicinal in this form will not be rapidly destroyed in the stomach, will not cause nausea or other irritation, and can be given irrespective of meals. It is particularly well adapted to pediatric use since children may take it .at any suitable time. No efiort need be made to predetermine a childs diet for the sake of administering the medicinal whereas most products previously available, erythromycin, for example, had to be given on a tasting stomach for maximum results. Since pilules can be mixed with food, the tendency of small children to 3,081,233 Patented Mar. 12, 1963 ice resist the administration of medicine is minimized. These pilules are effective enough to be given irrespective of mealtime and also are appreciably better therapeutically. In the case of medicinals absorbed into the blood, higher and more consistent blood levels, as well as more prolonged blood levels, are obtained with these pilules than with similarly coated larger dosage forms. The reason for this is unknown. Several reasons have been hypothesized but none has yet been substantiated. However, it is clear that superior therapeutic results are obtained with the dosage form of the present invention.
The enteric pilules can be formulated into a variety of finished pharmaceutical forms, for example, packets, twopiece hard gelatin capsules which can be sealed, one-piece sofit gelatin capsules, liquid suspensions, and the like.
In one embodiment of the invention the pilules are prepared by rolling the desired medicinal on moistened pill starters until small pills (pilules) are produced. The pilules are dried and subsequently coated with the enteric coating material.
A large number of medicinal agents can be prepared in the dosage forms of the present invention. Although the reasons for enteric coating these materials are different, the advantages inherent in the dosage form of the present invention are the same for each of these materials, i.e., quicker, better land/or more consistent therapeutic results are obtained in the dosage form of the present invention. For medicinals, such as erythromycin and penicillin, which are absorbed into the blood stream these advantages show up as quicker, higher and/or more consistent blood levels. These advantages together with advantages in actual use, such as adaptability to pediatric use, case of ingestion, innocuousness, and administration irrespective of mealtime, result in an ideal dosage form for a large number of medicinal materials, including the following (the reasons given are specific and in addition to the foregoing):
(a) Sedativesphenobarbital, sodium pentobarbital, cyclopentenylallylbarbituric acid, etc, to overcome bitter taste.
(b) Antipyreticsaspirin, salicylamide, sodium salicylate, etc, to overcome bitter taste, reduce gastric irri-. tation, and improve stability.
(0) Antibiotics-erythromycin, tetracycline, penicillin and the like, to avoid destruction in the stomach and improve taste.
(d) Antispasmodiosatropine, methscopolamine bromide, methscopolamine bromide with phenobarbital, to improve taste.
(e) Nutritional agents-multiple vitamins to improve taste and stability.
(f) Hematinics-ferrous sulfate, B intrinsic factor, etc, to reduce gastric irritation, eliminate discoloration of teeth and improve taste.
(g) Laxative-prune powder, to improve taste.
(h) Anthelmintics-santonin, piperazine citrate, etc., to improve taste, reduce irritation in mouth and stomach.
(i) Expectorant-arnmonium chloride, to improve taste and reduce gastric irritation.
(j) Hormones-adrenocorticosteroids, for example, 6a-methylprednisolone, hydrocortisone, and 9a-fiuoro- 16a-hydroxyprednisolone; androgenic steroids, for example, methyltestosterone, and 9a-fluoro-llp,l7fi-dihydroxy-17a-methyl-4-androstene-3-one; estrogenic steroids,
for example, l7fi-estradiol and 17-ethinyl, 3,17-cstradiol; and progestational steroids, for example, 17a-hydroxyprogesterone acetate, 6ct-methyl-17a-hydroxyprogesterone 17-acetate, and l7a-ethinyl-19-nortestosterone; to attain prolonged blood levels.
(k) Psycic energizer agents, for example, indole, 3-(2-aminopropyl)-, acetate and indole, 3-(2-aminobutyl)-, acetate, to attain prolonged absorption.
(1) Antimony potassium tartrate, to attain prolonged absorption.
Many non-toxic acidic enteric materials are suitable for the novel dosage forms of the present invention. In general such enteric materials serve the purpose of resisting disintegration of the coating until the pilules pass through the stomach into the intestine. Illustrative enteric materials and mixtures containing such materials include keratin, formalized gelatin, calcium alginate, shellac and like naturally occurring resinous substances, cellulose acetate phthalate, starch acetate phthalate, amylose acetate phthalate, partially hydrolyzed styrene-maleic anhydride copolymer, styrene-maleic acid copolymer, polyvinyl acetate phthalate, and polyvinyl hydrogenphthalate; shellacwool fat, shellac-caster oil, shellac-cetyl alcohol, shellacammonia, shellac-ammonia-alcohol; and the like.
The size of the finished pilules is very important. The size of the pill starters depends upon the finished size of the pilules to be produced and the amount of the other ingredients to be used therein. The amount of active material and the thickness of the enteric coat is adjusted to obtain a pilule not exceeding about 0.1 inch in diameter. It is preferred that the finished pilule range in size between about 0.04 and about 0.085 inch in diameter. The finished pilule size is a critical feature of the present invention.
In a more specific embodiment of the present invention an unweighed quantity of bolted sucrose (30 40 mesh) is placed in a revolving pill tub and moistened with a spray of deionized or distilled water until uniformly moistened. Uniformity in size of the bolted sucrose is more important at this stage than is the relative size of the sucrose granules. A small amount of a homogeneous mixture of talc, starch and sucrose (20:5:1) is dusted on the moistened sucrose. The tale, starch, sucrose mixture rolls onto the moistened sucrose. The contents of the pill tub are alternately water-sprayed and powder-dusted until spherical masses, called pill starters, are produced. The smaller spheres, which are separated from the larger spheres by screening during processing, are returned to the pill tub and brought up to proper size by the above described method. Those spheres which are out of shape at this point are preferably discarded. Only round, smooth starters are desirable.
A sufficient number of the spheres (or pill starters) of the proper size are placed in a revolving pill tub and sprayed with distilled or deionized Water until the pilules are uniformly moistened. A homogeneous mixture of the desired medicinal (e.g., erythromycin) three parts, talc 7.5 parts, starch two parts and sucrose one part, is dusted on the moistened pill starters. Again the water spraying and powder dusting are repeated alternately until the pilules are of the proper size. The pilules are air dried and then assayed for content of the active material.
Afterthe pilules have dried and the content of medicinal has been determined, the pilules are given several coats of an enteric material, using tale for dusting. Thus the finished pilules are built up from an inert core by adding 1) a layer containing a medicinal agent, and (2) an outer layer containing a single, non-toxic, acidic, enteric film-forming material.
In all cases approximately nine-tenths of the finished enteric coated pilules must resist artificial gastric juice (pH 1.2) for at least sixty minutes. The coatings designed to make the medicament rapidly available should disintegrate within sixty minutes in pH 6.8 buffer solution (citrate phosphate buffer) at 37 degrees Centigrade when subject to controlled and constant agitation in the buffer solutions. The coatings designed to provide prolonged availability of the medicament should disintegrate over a period of from about one to about seven hours in buffers from pH about 3.0 to about 8.0.
The enteric coated pilules can be sugar coated if desired and are now ready for therapeutic use. They may be mixed with various foods and their size is such that the average person taking the'pilules will be unaware of their presence in the food. Therapeutic doses are generally prepared in packets and capsules to better control the amount of each dose. Pilules containing one active material may also be mixed with other pilules containing other active materials for combined treatment with two or more active materials.
While it is not believed to be absolutely essential that the dosage form of the present invention be limited to spherical pilules from the standpoint of therapeutic results, it is desirable for other reasons. Appearance is better when the individual units are uniform. The dosage of active ingredient is easier to control when the units are uniform. The thickness of the enteric coat and the uniformity of the enteric coat are more difficult to control for irregularly shaped solids. Moreover, the size of the units is easier to control if prepared in a uniform manner, and spherical units are easier to administer and less irritating.
The following examples are illustrative of the process and product of this invention and are not to be construed as limiting.
EXAMPLE 1 Erythromycin Pilules of the pill tub are alternately water sprayed and powder dusted until spherical masses, called pill starters, having a diameter between 0.040 and 0.050 inch, are produced. The smaller spheres are separated from the larger ones by screening during processing. They are returned to the pill tub and brought up to the proper size by the above described method. Those spheres which are out of shape at this point are discarded. Only round, smooth starters are used to form pilules.
To prepare 50,000,000 pilules the following types and amounts of ingredients would be required:
Pill starters 50,000,000. Erythromycin crystalline base 59 lbs. 4 oz. Talc, bolted 224 lbs. Starch, bolted 64 lbs. Cane sugar powder, U.S.P 32 lbs. Color 1 lb.
The pill starters are placed in a revolving pill tub and sprayed with deionized water until the pilules are uniformly moistened. A homogeneous mixture of erythromycin three parts, talc 7.5 parts, starch two parts and sucrose one part, is dusted on the moistened pill starters. The water spraying and powder dusting are repeated until the pilules range in size from 0.065 to 0.071 inch in diameter. The pilules are air dried and assayed for erythromycin content.
After assay, the pilules are given several coats of cellulose acetate phthalate described in U.S. Patent 2,196,768 in an absolute alcohol-acetone solution having one to one ratio using tale for dusting. This procedure is continued until round and smooth pilules ranging in size from 0.065 to 0.085 inch in diameter are obtained.
The coating of the pilule should resist artificial gastric juice (pH 1.2) for at least sixty minutes and should disintegrate within sixty minutes in pH 6.8 butler solution (citnate phosphate buffer) at 37 degrees centigrade when subjected to controlled and constant agitation in the butler solutions.
The pilules are packaged in groups of 100, each packet supplying one therapeutic dose of about fifty milligrams (allowing for losses in manufacture and storage).
EXAMPLE 2 Salicylate Pilules Following the procedure of Example 1 pilules containing sodium salicylate as the active ingredient and coated with ammoniated shellac can also be prepared by substituting sodium salicylate for erythromycin and ammoniated shellac for cellulose acetate phthalate.
For 1,000,000 such pilules the following types and amounts of ingredients would be required:
Sodium salicylate, 3 lbs. 9 oz. 63 grs. Talc, 3 lbs. 5 oz. 313 grs.
Starch, 1 lb.
Cane sugar, 8 oz.
The superior therapeutic results obtained by the dosage form thus produced are illustrated by Table VI.
EXAMPLE 3 Ferrous Gluconate Pilules One million pilules containing ferrous gluconate as the ingredient are prepared from the following types and amounts of materials.
FERROUS GLUCONATE PILULES, 1,000,000
Ferrous gluconate, N.F., 3 lbs. 9 oz. 63 grs. Talc, U.S.P., 4 lbs. 8 oz.
Bolted starch, 1 lb. 4 oz. 250 grs.
Cane sugar powder, U.S.P., 10 oz. 125 grs.
Round, smooth pill starters are prepared as described in Example 1. One million of these pill starters are placed in a revolving pill tub and sprayed with deionized water until the pilules are uniformly moistened. A homogeneous mixture of ferrous gluconate 6.25 parts, talc seven parts, starch two parts and cane sugar one pant, is dusted on the moistened pill starters. The Water spraying and powder dusting are repeated until the pilules range in size from 0.065 to 0.075 inch in diameter. The pilules are air dried and assayed for ferrous gluconate content.
After assay, the pilules are replaced in a pill tub and given three coats of a thirty percent shellac in ethanol solution using talc for dusting. The pilules are then dried with a blast of hot air and two coats of a solution of gelatin, sucrose and water are applied with talc for dusting. A sufiicient number of coats of the gelatin-sucrose solution are applied using a mixture of precipitated calcium carbonate, talc and acacia, for dusting until 100 pilules laid end to end measure three and one-half inches. Then sufficient number of coats of a syrup solution with the car-bonate-talc-acacia mixture as a dusting powder are applied until the pilules are perfectly round. A syrup solution containing coloring material is applied to give the proper finished color to the pilules.
Those pilules having a diameter less than .065 inch or greater than .085 inch were discarded. One hundred pilules gave a therapeutic dose of 2.5 grains of ferrous gluconate.
EXAMPLE 4 Penicillin Pilules inch in diameter were discarded. By assay pilules thus produced contained 1286 units of penicillin per pilule.
I 6 Eighty such pilules provided a therapeutic dose of about 100,000 units of penicillin.
EXAMPLE 5 Tetracycline Hydrochloride Pilules ANIMAL DATA The following dosage forms were compared for blood levels in dogs:
-I. Tablet A--enteric coated erythromycin (commercially available product) Tablet 'B--non-enteric erythromycin Suspension-erythromycin as the ethyl carbonate in an orally acceptable vehicle (commercially available product) Pilules-enteric coated erythromycin II. III.
Eleven mongrel male dogs were used for this investigation. They are designated by number as 201, 202, 203, 204, 205, 210, 216, 218, 220, 222, and 224. In each experiment the dogs were starved eighteen hours prior to administration of the drugs. Except where otherwise indicated in the tables, each dog was given approximately 25 milligrams of erythromycin per kilogram of body weight orally and immediately thereafter fed a full can of dog food. The animals were then permitted to eat a regular laboratory diet ad lib throughout the day. Except where otherwise indicated, blood samples were taken shortly before the administration of the drug and usually every hour thereafter for a period of eight hours. Some dogs were run more than once on difierent days with the same or different dosage forms. Serum samples were assayed for erythromycin by a modification of the Rammelkamp (serial dilution) method employing Streptococcus hemolyticus as the test organism. The results are presented in the following tables (I through VI) and are given in terms of micrograms of erythromycin per milliliter of serum. Essentially, the tables are arranged and numbered in the same order as the dosage terms listed immediate, higher and more consistent blood levels.
TABLE I.TABLET A (ENTERIC COATED) Time (hours) 201 201 202 202 203 TABLE II.'IABLET B (UNCOATED) Time (hours) 201 202 203 Tables I, II, and III show that the maximum blood level which can be reasonably expected from the usual dosage forms is about one microgram of erythromycin per milliliter of serum and that the maximum is not obtained until the fourth hour or later.
TABLE IV.ENTERIC COATED PILULES Hour Dog 204 Dog 205 Dog 210 Dog 220 Dog 222 Although Table TV shows that the enteric coated pilules of the present invention are superior in many respects to the other dosage forms, the most striking difference is the fact that after one hour the enteric coated pilules give four times as high a blood level as the enteric coated tablets.
A similar experiment has been conducted with penicillin as the active ingredient in the dosage form prepared in the manner described in Example 4. Regular sized gelatin capsules were compared with uncoated pilules and enteric coated pilules. Again the dosage form of the present invention proved to be superior to the other forms in providing more immediate, higher and more consistent blood levels. The data are summarized in Table V.
TABLE V.SERUM LEVELS OF PENICILLIN IN DOGS FOL- LOWING ORAL ADMINISTRATION OF GELATIN CAP- SULES, COATED AND UNCOATED PILULES Dog 204 Dog 222 Hours Gelatin Uncoated Enterlc Gelatin Uncoated Enteric capsules pilules coated capsules pilules coated pilules pilules These data show at least a two fold increase in blood levels for the enteric pilules of the invention.
Still another experiment was conducted with the pilules containing sodium salicylate and described in Example 2. The plasma levels of salicylic acid in blood from starved adult female dogs were determined by oral administration of fifty milliliters of 0.1 normal hydrochloric acid followed by either the ammoniated shellac coated tablets or ammoniated shellac coated pilules given in a single No. 11 gelatin capulse (veterinary /2 oz. capsule, Eli Lilly and Company).
The sodium salicylate was administered at the level of 113 mg./ kg. of body weight. Four five grain tablets contained about 1300 milligrams of sodium salicylate while some 700 odd pilules were used to give 1300 milligrams of the drug. These two drug preparations gave similar disintegration times in vitro. The data obtained, summarized in Table VI, gives striking evidence of quicker,
form of TABLE VI 7 Salicylic acid/ml. plasma Do Dose type 1 hr. 2 hrs. 3 hrs. 5 hrs. 7 hrs.
A Tablets..- 0 5 5 147 154 Pilules 122 134 146 155 B Tablets 4 8 22 27 Pilules. 102 172 177 172 163 C Tablets 0 4 4 22 38 Pilules. 78 126 155 137 134 D Tablets. 0 0 0 11 35 Pilules. 67 137 179 193 186 [Average ranges for tablet vs. pilules in dogs] Average 7 salicylic acid/ml. plasma Dose 1 hr. 2 hrs. 3 hrs. 5 hrs. 7 hrs.
Tablets l 2 8 52 81 (0-4) (0-8) (0-22) (11-147) (35-154) Pilules 83 161 162 159 HUMAN USE The experiments given above in animals have been duplicated in humans, and the results have reaflirmed the conclusions that enteric coated pilules give higher, more immediate, and/ or more consistent blood levels than other dosage forms containing the same active material.
In general it should be noted that with all enteric coated dosage forms, there is a delay in the onset of maximum average blood levels as compared with nonenteric forms when the dosage form is administered with or immediately after meals. This is due to the additional time required for emptying the stomach following a meal providing an opportunity for the enteric coat to disintegrate in the upper intestine. When such dosage forms are administered on an empty stomach, peak blood levels are attained much more rapidly. In either case, however, the smaller pilules of the present invention give more efficient utilization of active material in providing higher, more consistent and more immediate blood levels than either larger dosage forms or suspensions.
Since the dosage form of the present invention is believed to be especially adaptable to pediatric use, it was tested on a group of eighteen children ranging in age from four months to fourteen years to test for patient acceptance. Among the various foods used as vehicles were pureed peaches, carrots, pears, pablum, apple sauce, beef, potatoes, rice, green beans, tomatoes, ice cream, soup, chocolate pudding, juice, and cereal. In general, acceptance was good, and the studies show that the pilules should be mixed with food that does not require mastication, such as pureed fruits, pudding, juice and the like.
The enteric coated erythromycin pilules were used to treat five children under two years of age at a dose of five milligrams per pound. The pilules were administered on a dry spoon or mixed with pudding and were taken without objection by the children. The following Table VII summarizes the blood levels obtained in micrograms of erythromycin per milliliter of blood.
Tables VIII and IX illustrate the superiority of the pilules over a comparable suspension when administered to children.
TABLE VIII.ERYTHROMYCIN PILULES [Single dose, 5 mg./lb.]
Blood levels, meg./m1. Age Weight Dose,
in lbs. mg.
1 hr. 2 hrs. 3 hrs. 4 hrs. 5 hrs. 8 hrs.
Average 24 4. 4 1.7 2.1 2. 8 52 Ratio 2 3/4 212 4/4 2/2 2/2 4/4 1 No reading taken wherever appear. 1 Fractions indicate the ratio of individuals with demonstrable levels to the total number of individuals in the group.
TABLE IX.ERYTHROMYCIN SUSPENSION prednisollone are prepared from the following types and [Single dose, 6.5 mg./lb.] amounts of ingredients:
\ [Pill starters prepared as in Example 1 (average diameter 0.0460047 in.), 50,000,000] Blood level, mcgJml. 25 Age Weight Dose, M d 1 in s. mg. e ieina agent mixture Lb 1 hr. 3 hr. 5 hr. 8 hr. S OZ 6a-methylprednisolone, micronized 3 6 118 Patient: Starch, bolted 6 2 335 1 25 yr 32 200 .6 1 1 1 Sucrose, powdered a 3 1 16s 18 100 .s .15 .1 1 Tale 14 7 166 40 250 1 1 .1 1 v Ethylene oxide-polypropylene glycol conden- 46 300 12 11 55 1 sation product 1 4 179 31% 200 76 .5 .32 19 32% 200 1 1 1 1 1 Pluronic F458, Wyandotte Chemical Company.
Average 131% .312 .zlg 1 Ram I I 35 The 6a-met-hylpredn1solone and an equal amount of the starch are uniformly mixed and the mixture is micronized. fifi figigtitifitii fi fi ififii gf fi ifit gfifig 1th demonstrable levels The mixture is then blended with the remaining starch and other ingredients and bolted through number 11 Table X provides further blood level data comparing cloththe dosage forms of the present invention with other a. dosage forms now available to the art. The superiority of the enteric coated pilules illustrated by higher, more immediate and more consistent blood levels is clearly Coating solution Lbs. Oz. Grs.
Hydrolysed styrene-maleio anhydride copolymer apparent from an examination of the data. Probably the M I 1 1 18 12 13 283 most striking thing shown in the table is the fact that the i i fi g g 2$; (1mm 2 1 $52 enteric coated pllules of the present 1nvent1on after two hours give three times as high a blood level as the small, unenteric l r The copolymer is dissolved in the alcohol and the min- TABLE X.OOMPARISON OF ERYIHROMYCIN BLOOD LEVELS AT VARIOUS INTERVALS AFTER ORAL ADMINISTRATION OF ERYTHROSULFA PREPARATIONS [Dose: 400 mg. erythromycin (about 2.5 mg./lb.). Time: V2 hour before breakfast] Blood level at intervals, hours Preparation Erythroruycin enteric pilules with triple sulfa pilules Average range .458 .263 182 .114 .079 Ratio (0) 1 0. 81 0-. 440 0-. 480 .072.236 .046-.144 8/9 8/9 8/9 9/9 9/9 Enteric coated erythromyein tablets laminated with Average range .3 49 .121 .063 .054 triple Sums, Ratio 0 1 0-1. 34 0-. 654 .oso-. 22 0-. 0-. 1 8/10 9/10 10/10 8/10 9/10 Erythromycin with triple sulfas flavored granules (not Average rang .174 47 31 ent rie). Ratio (2) l 0-. 256 0-. 256 0-1.06 0-, 230 0 1g6 5/10 7/10 7/10 7/10 4/10 Dn Average ran 086 045 058 031 R 0 456 0-. 254 0-. 098 0-.1 0- 082 A 049 046 0g 0 Er throm cin with tri 1e sulfas oral sus ension verage range 19 y y p p Ratio 0) 07- 280 0-..12 o .1o2 o- 1 0-. 08 10/10 6/10 8/10 5/10 3/10 X Fractions indicate the ratio of individuals with demonstrable levels to the total number of individuals in the group.' Number in parentheses indicates number of individuals in the group who had no detectable erythromycm levels at an; interval.
EXAMPLE 6 eral oil is added. It is preferred to use 1 1b. 8 ozs. 297 Steroid Pilules grs. of di-n-di butylphthalate as plastioizer in the coating 50,000,000 enteric coated pilules containing 6a-methyl 75 solution.
The ingredients are uniformly mixed using a No. 12 wire in the mixer.
Directions: The pill starters are sprayed in a revolving pill tub with deionized water until uniformly moistened.
The medicinal agent mixture is dusted on the moistened starters. The spraying and dusting are repeated until the average diameter of the pilules is from 0.048-0.049 in. The pilules are air dried and assayed tor steroid content.
The assayed pilules are coated with the coating solution using the magnesium stearate-talc mixture as dusting powder, until the average diameter is from 0.0510.052 in. The coated pilules are assayed for steroid content.
The coated pilules are encapsulated into two-piece hard gelatin capsules each containing 4 mgs. of 6u-methylprednisolone in the form of 140 enteric-coated pilules.
The oral administration to humans of one to two capsules daily provides beneficial results with lowered incidence of side eifects in rheumatoid arthritis. Advantageous, consistent blood levels of 17-OH corticosteroids are obtained in the oral treatment of addisonian disease.
EXAMPLE 7 Antimony Potassium Tartrate Pilules 10,000,000 pilules are prepared from the following types and amounts of materials:
[Pill starters prepared as in Example 1 (average diameter of 600 starter is 0.041 in.), 10,000,000]
In a revolving tub the starters are sprayed until uniformly wet with a 1% aqueous solution of the polyoxyethylene sorbitan monolaurate.
A homogeneous mixture of the antimony potassium bitartrate, the cane sugar, starch and talc is dusted on the wet starters. The spraying and dusting are repeated until the average diameter of 600 pilules is about 0.048 in. The pilues are air dried and assayed for antimony potassium bit-artrate content.
A-fter assay, the pilules are given several coats of hydrolysed styrene-maleic anhydride copolymer in an anhydrous ethanol solution containing mineral oil and di-nbuty-l phthalate, using the magnesium stearate-talc mixture as a dusting powder. This procedure is continued until uniform spherical pilules with an average diameter of about 0.055 in. are obtained. Beneficial results are obtained in the oral treatment of dermal leishmaniasis at a daily dose of 3 to 4 capsules.
The pilules are encapsulated into two-piece hard gelatin capsules each containing 22 mgs. of the medicinal agent in the form of 160 pilules.
EXAMPLE 8 Psychic Energizer Pilules Following the procedure of Example 6, 1,000,000 enteric coated pilules are prepared from the following types and amounts of materials.
12 Pill starters prepared as in Example 1 (average diameter 0.042 in.) 1,000,000
Medicinal agent mixture:
Indole, 3-(2-aminobutyl)-, acetate gms 43.2 Starch, bolted gms 63.0 Sucrose, powdered gms 31.5 Talc, bolted gms 147.6 Ethylene oxide-polypropylene glycol condensation product gms 2.8
Coating solution:
Styrene-maleic acid copolymer gms 700 Ethanol anhydrous, denatured cc 4670 Di-n-butylphthalate gms 84 White mineral oil, viscosity 180 gms 140 Dusting powder:
Magnesium stearate, powdered gms Talc, bolted gms 420 Pluronic F-68, Wyandotte Chemical Company.
The average diameter of the enteric coated pilules is 0.052 in. pilules contain 5 mgs. of the medicinal agent.
EXAMPLE 9 Androgenic Steroid Pilules Following the procedure of Example 6, 10,000,000 enteric coated pilules are prepared from the following types and amounts of ingredients:
[Pill starters prepared as in Example 1 (average diameter 0.041 in.),
Coating solution:
Polyvinyl acetate nhthal'lte Ethanol anhydrous, denatured Di-n-butylphthalate White mineral oil, viscosity 180.--
Dusting powder:
Magnesium stearate, powdered 1, 280 Tale, bolted 512 The average diameter of the enteric coated pilules is 0.055 in. pilules contain 10 mg. of the therapeutically active ingredient.
The oral administration to male humans of one capsule daily provides beneficial results in the treatment of androgen deficiencies.
This application is a continuation in part of co-pending application Serial Number 496,344, filed March 23, 1955, now abandoned.
What is claimed is:
1. An oral pharmaceutical preparation containing a plurality of enteric-coated pilules each of which measures not more than about 0.1 inch in diameter, is spherical, and has a uniform thickness of enteric coating and comprises (a) a medicinal agent and (b) a coating of a single, non-toxic, acidic, enteric film-forming material surrounding said agent, the plurality providing a unit dose of the medicinal agent.
2. The preparation of claim 1 wherein the medicinal agent is a therapeutically active form of erythromycin.
3. The preparation of claim 1 wherein the medicinal agent is a therapeutically useful form of iron.
4. The preparation of claim 1 wherein the medicinal agent is a therapeutically active form of penicillin.
5. The preparation of claim 1 wherein the medicinal agent is a therapeutically active form of a salicylic acid salt.
6. The preparation of claim 1 wherein the medicinal agent is a therapeutically active form of a tetracycline.
7. The preparation of claim 1 wherein the medicinal agent is a therapeutically active form of a steroid hormone.
8. The preparation of claim 1 wherein the enteric filmforrning material is cellulose acetate phthalate.
9. The preparation of claim 1 wherein the enteric film-forming material is hydrolyzed styrene-maleic anhydride copolymer which is more than fifty percent hydro- 1yzed.
10. The preparation of claim 1 wherein the enteric film-forming material is styrene maleic acid copolymer.
11. The preparation of claim 1 wherein the pilules measure between about 0.04 and 0.085 inch in diameter.
12. A process for preparing a plurality of spherical enteric-coated pilules which comprises preparing uniform spherical pill starters, applying thereto a coating of a medicinal agent which is advantageously administered orally in enteric-coated form and applying a coating of a single, non-toxic, enteric film-forming material, each step being so carried out as to provide pilules measuring not more than about 0.1 inch in diameter.
13. The process of claim 12 wherein the pilules measure between about 0.04 and about 0.085 inch in diameter.
14. An oral pharmaceutical capsule containing a plurality of enteric-coated pilules each of which measures not more than about 0.1 inch in diameter, is spherical, and has a uniform thickness of enteric coating and comprises (c z) 6a-methyleneprednisolone and (b) a coating of hydrolyzed styrene-maleic anhydride copoly-mer as the single, non-toxic, acidic, enteric film-forming material surrounding said 6a-methylprednisolone.
15. The capsule of claim 14 wherein the plurality of pilules contains about 4 mgs. of 6a-methylprednisolone.
16. An oral pharmaceutical capsule containing a plurality of enteric-coated pilules each of which measures not more than about 0.1 inch in diameter, is spherical, and has a uniform thickness of enteric coating and comprises (a) a medicinal agent and (b) a coating of a single, non-toxic, acidic, enteric film-forming material surrounding said agent, the plurality providing a unit dose of the medicinal agent.
17. An oral pharmaceutical packet containing a plurality of enteric-coated pilules each of which measures not more than about 0.1 inch in diameter, is spherical, and has a uniform thickness of enteric coating and comprises (a) a medicinal agent and (b) a coating of a single,
' non-toxic, acidic, enteric film-foaming material surrounding said agent, the plurality providing a unit dose of the medicinal agent.
References Cited in the file of this patent UNITED STATES PATENTS 2,553,544 Bogin May 22, 1951 2,553,806 Bogin -a May 22, 1951 2,738,303 Blythe Mar. 13, 1956 2,866,735 Himelick Dec. 30, 1958 FOREIGN PATENTS 109,438 Australia Dec. 2 2, 1939 644,759 Germany May 112, 1939 428,941 Great Britain May 22, 1935 715,305 Great Britain Sept. 8, 1954 OTHER REFERENCES New and Nonoflicial Remedies, 1955, I. B. Lippincott Co.,' pp. 188-189.
Claims (1)
1. AN ORAL PHARMACEUTICAL PREPARATION CONSISTING A PLURALITY OF ENTERIC-COATED PLULES EACH OF WHICH MEASURES NOT MORE THAN ABOUT 0.1 INCH IN DIAMETER, IS SPHERICAL, AND HAS A UNIFORM THICKNESS OF ENTERIC COATING AND COMPRISES (A) A MEDICINAL AGENT AND (B) A COATING OF A SINGLE NON-TOXIC, ACIDIC, ENTERIC FILM-FORMING MATERIAL SURROUNDING SAID AGENT, THE PLURALITY PROVIDING A UNIT DOSE OF THE MEDICINAL AGENT.
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US2553806A (en) * | 1950-07-12 | 1951-05-22 | Parke Davis & Co | Enteric composition and method of making same |
GB715305A (en) * | 1952-07-18 | 1954-09-08 | Smith Kline & French Internat | Improvements in or relating to sympathomimetic preparation |
US2738303A (en) * | 1952-07-18 | 1956-03-13 | Smith Kline French Lab | Sympathomimetic preparation |
US2866735A (en) * | 1954-03-18 | 1958-12-30 | Upjohn Co | Therapeutic composition of matter |
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US3265630A (en) * | 1958-12-22 | 1966-08-09 | Ncr Co | Encapsulating lipophilic material by coacervation |
US3132075A (en) * | 1960-10-17 | 1964-05-05 | Upjohn Co | Solid medicinal dosage forms coated with hydroxyethylcellulose and hydrolyzed styrene-maleic anhydride copolymer |
US3143472A (en) * | 1961-09-25 | 1964-08-04 | Lilly Co Eli | Enteric compositions |
US3247066A (en) * | 1962-09-12 | 1966-04-19 | Parke Davis & Co | Controlled release dosage form containing water-swellable beadlet |
US3242049A (en) * | 1963-05-20 | 1966-03-22 | Ncr Co | Process for making enterically useful complex of spiramycin and product thereof |
US3369968A (en) * | 1963-12-03 | 1968-02-20 | Walton J. Smith | Composition and method of absorbing gas in teh intestine |
US3383283A (en) * | 1964-01-24 | 1968-05-14 | Merck & Co Inc | Medicinal pellets coated with overlapping porous fatty acid leaflet layers |
US3437728A (en) * | 1964-06-15 | 1969-04-08 | Diwag Chemische Fabriken Gmbh | Protracted release pharmaceutical compositions |
US3400185A (en) * | 1965-04-08 | 1968-09-03 | Bristol Myers Co | Agglomeration of smaller pharmaceutical particles into larger microspherules and enteic-coating thereof |
US3891752A (en) * | 1966-04-25 | 1975-06-24 | Schmid Lab | Polyenic macrolide compositions and methods of use |
US3488417A (en) * | 1966-08-26 | 1970-01-06 | Philips Corp | Veterinary preparations having a coating resistant to the rumen contents |
US3688763A (en) * | 1969-07-28 | 1972-09-05 | Raymond Cromarty | Diagnostic device and method |
FR2184902A1 (en) * | 1972-05-18 | 1973-12-28 | Sanol Arznei Schwarz Gmbh | |
US4180064A (en) * | 1972-12-27 | 1979-12-25 | Alza Corporation | System for delivering agent to environment of use over prolonged time |
US3914402A (en) * | 1973-06-14 | 1975-10-21 | Alza Corp | Ophthalmic dosage form, for releasing medication over time |
US3975513A (en) * | 1973-09-06 | 1976-08-17 | Gewerkschaft Victor Chemische Fabrik | Sustained-release tablet for prophylaxis against trace element deficiency diseases |
US4150111A (en) * | 1974-05-28 | 1979-04-17 | Allister Warren | Enteric coated magnesium chloride |
US4177254A (en) * | 1976-01-02 | 1979-12-04 | Beecham Group Limited | Orally administrable pharmaceutical composition |
US4147768A (en) * | 1976-09-13 | 1979-04-03 | Interx Research Corporation | Enteric coated digoxin and therapeutic use thereof |
US4152414A (en) * | 1978-08-18 | 1979-05-01 | Iowa State University Research Foundation, Inc. | Combination vaccine for swine dysentery and method of use |
US4152413A (en) * | 1978-08-18 | 1979-05-01 | Chromalloy American Corporation | Oral vaccine for swine dysentery and method of use |
US4152415A (en) * | 1978-08-18 | 1979-05-01 | Iowa State University Research Foundation, Inc. | Method of increasing the effectiveness of oral vaccination for swine dysentery |
US4289750A (en) * | 1978-10-16 | 1981-09-15 | Kopp Klaus F | Therapy of conditions which may be associated with altered renal function and dosage forms therefor |
US4173626A (en) * | 1978-12-11 | 1979-11-06 | Merck & Co., Inc. | Sustained release indomethacin |
US4726951A (en) * | 1978-12-22 | 1988-02-23 | Elan Corporation P.L.C. | New pharmaceutical forms for administration of medicaments by oral route, with programmed release |
US4609542A (en) * | 1978-12-22 | 1986-09-02 | Elan Corporation, P.L.C. | New pharmaceutical forms for administration of medicaments by oral route, with programmed release |
US4289751A (en) * | 1979-06-29 | 1981-09-15 | Merck & Co., Inc. | Effervescent enteric-coated formulation of soluble form of erythromycin and therapeutic use thereof |
US4249531A (en) * | 1979-07-05 | 1981-02-10 | Alza Corporation | Bioerodible system for delivering drug manufactured from poly(carboxylic acid) |
US4308251A (en) * | 1980-01-11 | 1981-12-29 | Boots Pharmaceuticals, Inc. | Controlled release formulations of orally-active medicaments |
US4367217A (en) * | 1980-01-12 | 1983-01-04 | Boehringer Ingelheim Gmbh | Dipyricamole sustained release forms comprising lacquer-coated particles and the preparation thereof |
US5013727A (en) * | 1980-03-20 | 1991-05-07 | Farmaceutisk Laboratorium Ferring A/S | Pharmaceutical composition and method for the treatment of colitis ulcerosa and Crohn's disease by oral administration |
US5041431A (en) * | 1980-03-20 | 1991-08-20 | Farmaceutisk Laboratorium Ferring A/S | Pharmaceutical composition and method for the treatment of colitis ulcerosa and Crohn's disease by oral administration |
US4980173A (en) * | 1980-03-20 | 1990-12-25 | Farmaceutisk Laboratorium Ferring A/S | Pharmaceutical composition and method for the treatment of colitis ulcerosa and Crohn's disease by oral administration |
US4960765A (en) * | 1980-03-20 | 1990-10-02 | Farmaceutisk Laboratorium Ferring A/S | Pharmaceutical composition and method for the treatment of colitis ulcerosa and Crohn's disease by oral administration |
US4451452A (en) * | 1980-11-29 | 1984-05-29 | Sandoz Ltd. | Pharmaceutical compositions containing biodegradable polymers |
US4615881A (en) * | 1980-11-29 | 1986-10-07 | Sandoz Ltd. | Pharmaceutical compositions |
US4587118A (en) * | 1981-07-15 | 1986-05-06 | Key Pharmaceuticals, Inc. | Dry sustained release theophylline oral formulation |
WO1983000284A1 (en) * | 1981-07-15 | 1983-02-03 | Key Pharma | Sustained release theophylline |
EP0080341A2 (en) * | 1981-11-20 | 1983-06-01 | A/S Alfred Benzon | Pharmaceutical multiple-units formulation |
EP0080341A3 (en) * | 1981-11-20 | 1983-09-14 | A/S Alfred Benzon | Pharmaceutical multiple-units formulation |
US4508702A (en) * | 1982-06-14 | 1985-04-02 | Key Pharmaceuticals, Inc. | Sustained release aspirin |
US4634587A (en) * | 1982-07-09 | 1987-01-06 | Key Pharmaceuticals, Inc. | Sustained release quinidine dosage form |
US4820521A (en) * | 1983-04-06 | 1989-04-11 | Eland Corporation P.L.C. | Sustained absorption pharmaceutical composition |
US4555399A (en) * | 1983-11-18 | 1985-11-26 | Key Pharmaceuticals, Inc. | Aspirin tablet |
US4874614A (en) * | 1985-03-25 | 1989-10-17 | Abbott Laboratories | Pharmaceutical tableting method |
US4863741A (en) * | 1985-03-25 | 1989-09-05 | Abbott Laboratories | Tablet composition for drug combinations |
US4755385A (en) * | 1985-07-10 | 1988-07-05 | Dr. Karl Thomae, Gmbh | Oral pharmaceutical preparations containing 9-deoxo-11-deoxy-9,11-[imino[2-(2-methoxyethoxy)-ethylidene]-oxy]-(9S)-erythromycin |
EP0208971A3 (en) * | 1985-07-10 | 1988-01-27 | Dr. Karl Thomae Gmbh | Solid galenical forms for oral application containing 9-deoxo-11-deoxy-9,11-(imino(2-(2-methoxyethoxy)ethyliden)-oxy)-(9s)-erythromycin, and process for their preparation |
EP0208971A2 (en) * | 1985-07-10 | 1987-01-21 | Dr. Karl Thomae GmbH | Solid galenical forms for oral application containing 9-deoxo-11-deoxy-9,11-(imino(2-(2-methoxyethoxy)ethyliden)-oxy)-(9S)-erythromycin, and process for their preparation |
US4752479A (en) * | 1986-05-27 | 1988-06-21 | Ciba-Geigy Corporaton | Multi vitamin and mineral dietary supplement with controlled release bioavailable iron |
BE1000434A5 (en) * | 1986-05-27 | 1988-12-06 | Ciba Geigy | Dietary supplement multiple vitamins and minerals several bioavailable iron containing controlled release. |
FR2601589A1 (en) * | 1986-05-27 | 1988-01-22 | Ciba Geigy Ag | DIETETIC SUPPLEMENT WITH SEVERAL VITAMINS AND SEVERAL MINERALS CONTAINING BIODISPONIBLE IRON WITH CONTROLLED RELEASE |
US4752470A (en) * | 1986-11-24 | 1988-06-21 | Mehta Atul M | Controlled release indomethacin |
US4961932A (en) * | 1987-10-26 | 1990-10-09 | Alza Corporation | Plurality of tiny pills in liquid dosage form |
US5030454A (en) * | 1987-10-26 | 1991-07-09 | Alza Corporation | Method for delivering drug in tiny pills in liquid carrier |
US4853229A (en) * | 1987-10-26 | 1989-08-01 | Alza Corporation | Method for adminstering tiny pills |
US20030012862A1 (en) * | 2001-07-16 | 2003-01-16 | Ayres Roger Ravi | Encapsulated prune powder to relieve constipation |
US20040191313A1 (en) * | 2003-03-05 | 2004-09-30 | Thomas Moest | Solid, accurately dosable pharmaceutical presentations for individual dispensing from dosing devices and methods thereof |
US20090162428A1 (en) * | 2007-12-24 | 2009-06-25 | I.P.S. International Products & Services S.R.L. | Immediate disintegration polyvalent polymeric matrix for modified release solid oral preparations and method of preparation thereof |
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