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US3859431A - Drug formulations - Google Patents

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US3859431A
US3859431A US321090A US32109073A US3859431A US 3859431 A US3859431 A US 3859431A US 321090 A US321090 A US 321090A US 32109073 A US32109073 A US 32109073A US 3859431 A US3859431 A US 3859431A
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active agent
alkali metal
physiologically active
capsules
carboxymethyl starch
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US321090A
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John Michael Newton
Geoffrey Rowley
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Lilly Industries Ltd
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Lilly Industries Ltd
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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
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4866—Organic macromolecular compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
    • A61J3/00—Devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms
    • A61J3/07—Devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms into the form of capsules or similar small containers for oral use
    • A61J3/071—Devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms into the form of capsules or similar small containers for oral use into the form of telescopically engaged two-piece capsules
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10S206/00—Special receptacle or package
    • Y10S206/828—Medicinal content

Definitions

  • This invention relates to pharmaceutical dosage forms. More particularly, this invention relates to a method for improving the rate of release of physiologically active agents from pharmaceutical capsules, and to pharmaceutical compositions adaptable for filling into such capsules, such capsules filled with such compositions having improved active agent release rate characteristics.
  • the two-piece capsule is normally made of gelatin, but other materials, such as methylcellulose and calcium alginate, which will dissolve in the gastro-intestinal tract and which are non-toxic can also be used.
  • the rate of release of a physiologically active agent from the capsule is affected by a number of parameters including the disintegration time of the capsule shell, the packing density of the materials in the capsule, the particle size of the materials and the nature of the active agent and the various diluents normally present to aid in obtaining accurate and uniform dosage in the capsule filling operation. While these parameters can frequently be optimized for any given pharmaceutical compositon so as to achieve as quick a release of the physiologically active agent as possible, it often happens that many such compositons show a relatively slow rate of release of the active agent and/or the rate of release is adversely affected by prolonged storage times, especially if stored at elevated temperatures.
  • it is an object of the present invention to provide a method of improving the rate of release of a physiologically active agent from a capsule.
  • the useful process of this invention comprises commingling an alkali metal carboxymethyl starch and a physiologically acitve agent in pharmaceutical compositons adapted for filling into capsules having an improved rate of release of said physiologically active agent.
  • alkali metal carboxymethyl starch in which sodium is the alkali metal, is represented by the following formula:
  • alkali metal derivatives such as lithium and potassium can be prepared by substituting the appropriate alkali metal hydroxide for the sodium hydroxide and the scope of'this invention encompasses such other alkali metal derivatives of carboxymethyl starch.
  • the alkali metal carboxymethyl starch useful in the novel process of this invention has from about 15 to about 35 carboxymethyl groups, preferably about 25 per glucose units. This means that the degree of substitution (DS) ranges from about 0.15 to 0.35, preferably being about 0.25, which indicates that in general one of the three hydroxyl groups in every fourth glucose unit has been substituted with an alkali metal carboxymethyl moiety. It will be recognized by the skilled starch chemist that there may be some glucose units whereon 2 or possibly all 3 of the hydroxyl groups have been substituted. Nevertheless, the alkali metal carboxymethyl starch useful in the instant invention will have approximately 15 to 35 carboxymethyl groups per 100 glucose units substituted on a hydroxyl moiety.
  • the amount of the alkali metal carboxymethyl starch needed to provide the improved rate of release of a is not limited.
  • pharmaceutically active agent from a capsule can vary within wide limits, and it appears that the quantity required may be inversely proportional to the solubility of such active agent.
  • the quantity required may be inversely proportional to the solubility of such active agent.
  • up to about 65 percent by weight of said carboxymethyl starch may be needed to obtain improved release rates of poorly soluble active agents, while an amount as low as 2 by weight may be adequateto produce the desired effect on a highly soluble drug.
  • a range of from about 8 to about 55 percent by weight of the alkali metal carboxymethyl starch is adequate.
  • the preferred alkali metal carboxymethyl starch for use in the present invention is a sodium carboxymethyl starch which, most advantageously, has a degree of substitution of about 25 carboxymethyl groups per I00 glucose units.
  • a pharmaceutical composition in capsule form having an improved rate of release characterised in that such composition contains from about 2 to about 65 precent by weight, based on the weight of the physiologically active agent present in the composition, of an alkali metal, preferably sodium, carboxymethyl starch having a degree of substitution of from 15 to 35, preferably about 25, carboxymethyl groups per 100 glucose units.
  • an alkali metal preferably sodium, carboxymethyl starch having a degree of substitution of from 15 to 35, preferably about 25, carboxymethyl groups per 100 glucose units.
  • composition may contain the active agent and carboxymethyl starch as the only ingredients or, if desired, other diluents may also be included such as those commonly used in conventional capsule formulations, for example lactose, dextrose, sucrose, sorbitol, mannitol, starch, sodium bicarbonate, methyl cellulose, sodium lauryl sulphate, polyoxyethylene sorbitan monolaurate and methyl and propyl hydroxybenzoates.
  • diluents such as those commonly used in conventional capsule formulations, for example lactose, dextrose, sucrose, sorbitol, mannitol, starch, sodium bicarbonate, methyl cellulose, sodium lauryl sulphate, polyoxyethylene sorbitan monolaurate and methyl and propyl hydroxybenzoates.
  • physiologically active agent used in the compositions of the present invention does not appear to be critical to the operation of the invention, although, since the effect of the use of an alkali metal carboxymethyl starch is most noticeable with poorly soluble active agents the latter are likely to be the most commonly used active agents.
  • cardiovascular drugs such as bethanidine sulphate, methyldopa, penta-erythritol tetranitrate, cyclandelate, phenoxybenzamine hydrochloride, glyceryl trinitrate, ergotamine tartrate, diphenhydramine hydrochloride and dichloralphenazone
  • central nervous system drugs such as amylobarbital, aspirin, dextropropoxyphene hydrochloride, phenacetin, caffeine, pentazocine hydrochloride, indomethacin,
  • EXAMPLE 1 cent by weight, respectively, based onthe weight 'of said active agent, of sodium carboxymethyl starch (SCMS) containing approximately carboxymethyl groups per 100 glucose units.
  • SCMS sodium carboxymethyl starch
  • the capsules were suspended in a dissolving medium (N/lO hydrochloric acid) at 37C., and the time in minutes determined for 50 percent of the drug content to enter solution (T).
  • T The results were Amylobarbitone flufenamic acid, potassium p-aminobenzoate, pentobarbital sodium, ethchlorvinol, carbromal, propiomazine, methaqualone, diphenhydramine, heptabarbital, nitrazepam, quinalbarbital sodium, chlorpromazine, trifluoperazine, nortriptyline, hydroxyzine pamoate, chlordiazepoxide, ethinamate, amitriptyline, medazepam, methylpentynol carbamate, haloperidol, doxepin hydrochloride, prothipendyl hydrochloride, phensuximide, ethosuximide, pyrrobutamine, thenylpyr
  • the present invention is effected by commingling the desired physiologically active agent with the alkali metal carboxymethyl starch to provide a uniform blend.
  • Any of the conventional blending equipment such as ribbon mixers, paddle mixers, tumbling cones, twin shell blenders, verticle mixers, and the like can be employed to accomplish the commingling.
  • Other appropriate diluents, internal lucricants, preservatives, excipients, and the like can be added to the blender concurrently with said active agent and said carboxymethyl starch so that one operative blending step can be utilized, if desired, to accomplish the obejcts of this invention.
  • the resulting pharmaceutical composition is EXAMPLE 2
  • various drugs were mixed with a diluent (starch/lactose in a ratio of 1:1 and a lubricant (magnesium stearate).
  • a diluent starch/lactose in a ratio of 1:1
  • a lubricant magnesium stearate
  • capsules containing SCMS can be stored at elevated temperatures for long periods oftime without encountering any substantial retardation in the rate of release of drugs therefrom, which retardation, as can also be seen from the above results, frequently occurs with conventional encapsulated drug formulations. Indeed, in all instances, the above tests show an improvement in the rate of release of drug after storage for 14 or 28 days when from 10 to 50 percent SCMS is incorporated into the capsules. In most cases, a marked improvement in the T is also seen in newly formulated capsules containing SCMS.
  • a pharmaceutical two-piece hard gelatin capsule comprising a physiologically active agent commingled with an amount, of from about 2 to about 65 percent by weight of the physiologically active agent, as a release rate improving quantity of an alkali metal carboxymethyl starch.
  • sodium is the alkali metal carboxymethyl starch and is present in an amount of from about 2 to about 65 percent by weight of the physiologically active agent.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Medicinal Preparation (AREA)

Abstract

Method for improving the rate of release of physiologically active agents from capsules, and pharmaceutical compositions adapted for filling into capsules, said capsules filled with such compositions having improved rates of release of the physiologically active agent therefrom.

Description

United States Patent Newton et al.
[ 1 Jan. 7, 1975 DRUG FORMULATIONS [73] Assignee: Lilly Industries Limited, London,
England [22] Filed: Jan. 4, 1973 [21] Appl. No.: 321,090
[30] Foreign Application Priority Data Jan. 12, 1972 Great Britain 1377 [52] US. Cl 424/37, 424/361, 206/84 [51] Int. Cl. A6lj 3/07 [58] Field of Search 424/37, 361, 362
[56] References Cited UNITED STATES PATENTS 2,851,453 9/1958 Kennon et al. 260/232 3,034,911 5/1962 McKee et al. 106/210 3,133,863 5/1964 Tansey 424/19 3,427,378 2/1969 Henderson et a1 424/14 3,444,290 5/1969 Wai 424/362 3,679,794 7/1972 Bentholm et a1. 424/362 X FOREIGN PATENTS OR APPLICATIONS 721,944 3/1969 Belgium Primary Examiner-Shep K. Rose Attorney, Agent, or Firm-Ralph W. Ernsberger; Everet F. Smith [5 7] ABSTRACT Method for improving the rate of release of physiologically active agents-from capsules, and pharmaceutical compositions adapted for filling into capsules, said capsules filled with such compositions having improved rates of release of the physiologically active agent therefrom.
5 Claims, No Drawings BACKGROUND OF THE INVENTION 1. Field Of The Invention This invention relates to pharmaceutical dosage forms. More particularly, this invention relates to a method for improving the rate of release of physiologically active agents from pharmaceutical capsules, and to pharmaceutical compositions adaptable for filling into such capsules, such capsules filled with such compositions having improved active agent release rate characteristics.
2. Discussion of the Prior Art Among the various ways of orally administering a physiologically active agent to humans, the use of a two-piece capsule as a carrier for a unit dose of such active agent is one of the most common. The two-piece capsule is normally made of gelatin, but other materials, such as methylcellulose and calcium alginate, which will dissolve in the gastro-intestinal tract and which are non-toxic can also be used.
The rate of release of a physiologically active agent from the capsule is affected by a number of parameters including the disintegration time of the capsule shell, the packing density of the materials in the capsule, the particle size of the materials and the nature of the active agent and the various diluents normally present to aid in obtaining accurate and uniform dosage in the capsule filling operation. While these parameters can frequently be optimized for any given pharmaceutical compositon so as to achieve as quick a release of the physiologically active agent as possible, it often happens that many such compositons show a relatively slow rate of release of the active agent and/or the rate of release is adversely affected by prolonged storage times, especially if stored at elevated temperatures.
Accordingly,,it is an object of the present invention to provide a method of improving the rate of release of a physiologically active agent from a capsule.
It is a further object of this invention to provide pharmaceutical compositions adapted for filling into capsules and capsules filled with such compositions having improved active agent release properties.
SUMMARY It has now been discovered that the commingling of an alkali metal carboxymethyl starch, in an amount of from about 2 to about 65 percent by weight, based on the weight of a physiologically active agent, with said active agent provides a pharmaceutical composition adapted for filling into capsules which, when filled into such capsules, provides a pharmaceutical dosage form having improved active agent release rates.
DESCRIPTION OF THE PREFERRED EMBODIMENT The useful process of this invention comprises commingling an alkali metal carboxymethyl starch and a physiologically acitve agent in pharmaceutical compositons adapted for filling into capsules having an improved rate of release of said physiologically active agent.
An alkali metal carboxymethyl starch, in which sodium is the alkali metal, is represented by the following formula:
and is prepared by reacting starch with ch loroacetic acid in the presence of sodium hydroxide.
Other alkali metal derivatives, such as lithium and potassium can be prepared by substituting the appropriate alkali metal hydroxide for the sodium hydroxide and the scope of'this invention encompasses such other alkali metal derivatives of carboxymethyl starch.
The alkali metal carboxymethyl starch useful in the novel process of this invention has from about 15 to about 35 carboxymethyl groups, preferably about 25 per glucose units. This means that the degree of substitution (DS) ranges from about 0.15 to 0.35, preferably being about 0.25, which indicates that in general one of the three hydroxyl groups in every fourth glucose unit has been substituted with an alkali metal carboxymethyl moiety. It will be recognized by the skilled starch chemist that there may be some glucose units whereon 2 or possibly all 3 of the hydroxyl groups have been substituted. Nevertheless, the alkali metal carboxymethyl starch useful in the instant invention will have approximately 15 to 35 carboxymethyl groups per 100 glucose units substituted on a hydroxyl moiety.
The amount of the alkali metal carboxymethyl starch needed to provide the improved rate of release of a.
pharmaceutically active agent from a capsule can vary within wide limits, and it appears that the quantity required may be inversely proportional to the solubility of such active agent. Thus, based on the weight of such active agent present in the capsule, up to about 65 percent by weight of said carboxymethyl starch may be needed to obtain improved release rates of poorly soluble active agents, while an amount as low as 2 by weight may be adequateto produce the desired effect on a highly soluble drug. For most physiologically active agents, however, a range of from about 8 to about 55 percent by weight of the alkali metal carboxymethyl starch is adequate.
The preferred alkali metal carboxymethyl starch for use in the present invention is a sodium carboxymethyl starch which, most advantageously, has a degree of substitution of about 25 carboxymethyl groups per I00 glucose units.
According to a further aspect of the present invention, there is provided a pharmaceutical composition in capsule form having an improved rate of release characterised in that such composition contains from about 2 to about 65 precent by weight, based on the weight of the physiologically active agent present in the composition, of an alkali metal, preferably sodium, carboxymethyl starch having a degree of substitution of from 15 to 35, preferably about 25, carboxymethyl groups per 100 glucose units. The composition may contain the active agent and carboxymethyl starch as the only ingredients or, if desired, other diluents may also be included such as those commonly used in conventional capsule formulations, for example lactose, dextrose, sucrose, sorbitol, mannitol, starch, sodium bicarbonate, methyl cellulose, sodium lauryl sulphate, polyoxyethylene sorbitan monolaurate and methyl and propyl hydroxybenzoates.
The physiologically active agent used in the compositions of the present invention does not appear to be critical to the operation of the invention, although, since the effect of the use of an alkali metal carboxymethyl starch is most noticeable with poorly soluble active agents the latter are likely to be the most commonly used active agents.
The following non-limiting examples will illustrate the types of physiologically active agents to which the method of the present invention may be applied or which may be used in the pharmaceutical compositions of the present invention: cardiovascular drugs such as bethanidine sulphate, methyldopa, penta-erythritol tetranitrate, cyclandelate, phenoxybenzamine hydrochloride, glyceryl trinitrate, ergotamine tartrate, diphenhydramine hydrochloride and dichloralphenazone; central nervous system drugs such as amylobarbital, aspirin, dextropropoxyphene hydrochloride, phenacetin, caffeine, pentazocine hydrochloride, indomethacin,
paracetamol, codeine phosphate, mefenamic acid, as follows:
filled into the appropriate size capsule by conventional filling means to provide unit dose capsules having improved release rates of the physiologically active agent contained therein.
The present invention is further illustrated by the following examples.
EXAMPLE 1 cent by weight, respectively, based onthe weight 'of said active agent, of sodium carboxymethyl starch (SCMS) containing approximately carboxymethyl groups per 100 glucose units. The resulting pharmaceutical compositions were filled into two-piece hard gelatin capsules. The capsules were suspended in a dissolving medium (N/lO hydrochloric acid) at 37C., and the time in minutes determined for 50 percent of the drug content to enter solution (T The results were Amylobarbitone flufenamic acid, potassium p-aminobenzoate, pentobarbital sodium, ethchlorvinol, carbromal, propiomazine, methaqualone, diphenhydramine, heptabarbital, nitrazepam, quinalbarbital sodium, chlorpromazine, trifluoperazine, nortriptyline, hydroxyzine pamoate, chlordiazepoxide, ethinamate, amitriptyline, medazepam, methylpentynol carbamate, haloperidol, doxepin hydrochloride, prothipendyl hydrochloride, phensuximide, ethosuximide, pyrrobutamine, thenylpyramine, cyclopentamine, mebanazine, chlomipramine, dexamphetamine and imipramine hydrochloride; antibiotics such as tetracycline, novobiocin, chlortetracycline, oxytetracycline, phenthicillin, cephalexin, chloramphenicol, phenoxymethyl penicillin, clindamycin, oleandomycin, flucloxacillin, fusidic acid, paromomycin, erythromycin estolate, propionyl erythromycin, kanamycin sulphate, demethylchlortetracycline, lincomycin, nystatin, cloxacillin, ampicillin, doxycycline; as well as various other drugs such as clofibrate, D()penicillamine, nalidixic acid, acetohexamide, methylthiouracil, ephedrine sulphate, chlorprenaline, crotethamide and theophylline.
The present invention is effected by commingling the desired physiologically active agent with the alkali metal carboxymethyl starch to provide a uniform blend. Any of the conventional blending equipment, such as ribbon mixers, paddle mixers, tumbling cones, twin shell blenders, verticle mixers, and the like can be employed to accomplish the commingling. Other appropriate diluents, internal lucricants, preservatives, excipients, and the like can be added to the blender concurrently with said active agent and said carboxymethyl starch so that one operative blending step can be utilized, if desired, to accomplish the obejcts of this invention. The resulting pharmaceutical composition is EXAMPLE 2 In this example, various drugs were mixed with a diluent (starch/lactose in a ratio of 1:1 and a lubricant (magnesium stearate). To the resultant formulations was added 0, 10 or 50 percent by weight, based on the weight of the drug, of SCMS. The finished formulations were filled into hard gelatin capsules so as to give capsules containing the following quantities of ingredients:
Nominal mg. per Capsule Formu Drug lation Active SCMS Diluent Lubricant Refer cncc 500 0 300 8 l Ethinamate 400 40 200 7 2 460 230 46 8 3 I00 0 l50 2.5 4 Phenylbutazone 10 I40 2.5 5 100 50 I00 2.5 6
250 0 4 7 Penicillamine 250 25 I25 4 8 HCl 250 I25 25 4 9 -Continued Nominal mg. per Capsule Formu- Drug lation Active SCMS Diluent Lubricant Reference 250 150 4 10 Sulphadimidine 250 25 125 4 11 250 125 25 4 12 250 0 150 4 13 Acetohexamide 250 25 125 4 14 250 125 25 4 15 380 0 228 6 16 Paracetamol 380 38 190 6 17 380 190 38 6 18 Each of formulations l to 18 was divided into three groups. In respect of one group, the T (as defined above) was immediately measured whilst, in respect of the other two groups, the T was determined after storage of the capsules at 50C. for 14 and 28 days respectively. The following results were obtained:
Formu- T50 lation Refer- Initial 14 days at 50C. 28 days at 50C.
ence
1 50.9 min. 60 min. 60 min. 2 8.6 min. 7.2 min. 8.3 min. 3 5.8 min. 8.5 min. 7.3 min.
4 26.2 min. 60 min. 60 min. 5 24.7 min. 32.2 min. 18.8 min. 6 17.9 min. 20.0 min. 21.2 min.
7 5.9 min. 6.1 min. 6.9 min. 8 5.9 min. 5.3 min. 4.9 min. 9 6.4 min. 4.0 min. 3.9 min.
10 9.0 min. 20.2 min. 22.2 min. 11 8.4 min. 8.0 min. 9.7 min. 12 5.2 min. 4.9 min. 3.6 min.
13 60 min. 49 min. 60 min. 14 31.5 min. 30.5 min. 29.0 min. 15 18.6 min. 22.5 min. 19.3 min.
16 7.3 min. 17.9 min. 37.9 min. 17 7.6 min. 4.0 min. 9.2 min. 18 2.1 min. 3.0 min. 3.8 min.
From the above tests it will be noted that capsules containing SCMS can be stored at elevated temperatures for long periods oftime without encountering any substantial retardation in the rate of release of drugs therefrom, which retardation, as can also be seen from the above results, frequently occurs with conventional encapsulated drug formulations. Indeed, in all instances, the above tests show an improvement in the rate of release of drug after storage for 14 or 28 days when from 10 to 50 percent SCMS is incorporated into the capsules. In most cases, a marked improvement in the T is also seen in newly formulated capsules containing SCMS.
Since storage of drugs for short periods of 14 or 28 days at 50C. is recognised in the art as giving results equivalent to those that are obtained when the drugs are stored in room temperature for the usual periods encountered between manufacture and use of the drugs, it will be appreciated from the above results that the incorporation of an alkali metal carboxymethyl starch (of the type hereinbefore defined) into an encapsulated drug formulation provides a most useful means of improving the rate of release of the drug from the capsule.
What is claimed is:
l. A pharmaceutical two-piece hard gelatin capsule comprising a physiologically active agent commingled with an amount, of from about 2 to about 65 percent by weight of the physiologically active agent, as a release rate improving quantity of an alkali metal carboxymethyl starch.
2. The pharmaceutical two-piece hard gelatin capsule ofclaim 1, wherein the alkali metal carboxymethyl starch contains from 15 to 35 carboxymethyl groups per glucose units.
3. The pharmaceutical two-piece hard gelatin capsule of claim 1, wherein the alkali metal is sodium.
4. The pharmaceutical two-piece hard gelatin capsule of claim 1, wherein sodium is the alkali metal carboxymethyl starch and is present in an amount of from about 2 to about 65 percent by weight of the physiologically active agent.
5. The capsule of claim 1, wherein said physiologically active agent is ethinamate.

Claims (5)

1. A PHARMACEUTICAL TWO-PIECE HARD GELATIN CAPSULE COMPRISING A PHYSIOLOGICALLY ACTIVE AGENT COMMINGLED WITH AN AMOUNT, OF FROM ABOUT 2 TO ABOUT 65 PERCENT BY WEIGHT OF THE PHYSIOLOGICALLY ACTIVE AGENT, AS A RELEASE RATE IMPROVING QUANTITY OF AN ALKALI METAL CARBOXYMETHYL STARCH.
2. The pharmaceutical two-piece hard gelatin capsule of claim 1, wherein the alkali metal carboxymethyl starch contains from 15 to 35 carboxymethyl groups per 100 glucose units.
3. The pharmaceutical two-piece hard gelatin capsule of claim 1, wherein the alkali metal is sodium.
4. The pharmaceutical two-piece hard gelatin capsule of claim 1, wherein sodium is the alkali metal carboxymethyl starch and is present in an amount of from about 2 to about 65 percent by weight of the physiologically active agent.
5. The capsule of claim 1, wherein said physiologically active agent is ethinamate.
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Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4507276A (en) * 1982-08-20 1985-03-26 Bristol-Myers Company Analgesic capsule
WO1985003439A1 (en) * 1984-02-08 1985-08-15 R.P. Scherer Corporation Acetaminophen gelatin capsule providing rapid onset of therapeutic activity upon oral administration
US4620974A (en) * 1983-07-07 1986-11-04 American Home Products Corporation Pharmaceutical composition containing a liquid lubricant
US4728512A (en) * 1985-05-06 1988-03-01 American Home Products Corporation Formulations providing three distinct releases
US4777048A (en) * 1983-07-07 1988-10-11 American Home Products Corporation Pharmaceutical composition containing a liquid lubricant
US4794001A (en) * 1986-03-04 1988-12-27 American Home Products Corporation Formulations providing three distinct releases
US4832952A (en) * 1983-07-07 1989-05-23 American Home Products Corporation Pharmaceutical composition containing a liquid lubricant
US4904476A (en) * 1986-03-04 1990-02-27 American Home Products Corporation Formulations providing three distinct releases
US5037658A (en) * 1989-09-14 1991-08-06 Hoechst-Roussel Pharmaceuticals, Inc. Direct dry compressible acetaminophen composition
US5130140A (en) * 1989-09-14 1992-07-14 Hoeschst-Roussel Pharmaceuticals Inc. Method of making direct dry compressible acetaminophen composition
US5198228A (en) * 1989-09-14 1993-03-30 Hoechst-Roussel Pharmaceuticals Inc. Direct dry compressible acetaminophen tablet
EP0563697A3 (en) * 1992-04-03 1994-06-01 Nippon Kayaku Kk Cytarabine ocfosfate hard capsule
US20080286253A1 (en) * 2004-02-09 2008-11-20 Transfert Plus Societe En Commandite Composition Comprising Polymeric Material And Uses Thereof
US20190282519A1 (en) * 2018-03-19 2019-09-19 Cronus Research Labs Private Limited Pencillamine oral composition

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US3034911A (en) * 1959-03-25 1962-05-15 Nat Starch Chem Corp Tablet disintegrants
US3133863A (en) * 1961-03-10 1964-05-19 Strong Cobb Arner Inc Sustained release therapeutic tablet compositions comprising organic solvent-gelled gums
US3427378A (en) * 1965-02-12 1969-02-11 American Cyanamid Co Sustained release encapsulated formula
US3444290A (en) * 1965-02-15 1969-05-13 Biorex Laboratories Ltd Dosage unit forms for the administration of medicaments
US3679794A (en) * 1968-02-15 1972-07-25 Organon Nv Process for the manufacture of rapidly disintegrating solid dosage unit forms

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Publication number Priority date Publication date Assignee Title
US2851453A (en) * 1954-08-09 1958-09-09 Smith Kline French Lab Cellulose derivative product, compositions comprising the same and their preparation
US3034911A (en) * 1959-03-25 1962-05-15 Nat Starch Chem Corp Tablet disintegrants
US3133863A (en) * 1961-03-10 1964-05-19 Strong Cobb Arner Inc Sustained release therapeutic tablet compositions comprising organic solvent-gelled gums
US3427378A (en) * 1965-02-12 1969-02-11 American Cyanamid Co Sustained release encapsulated formula
US3444290A (en) * 1965-02-15 1969-05-13 Biorex Laboratories Ltd Dosage unit forms for the administration of medicaments
US3679794A (en) * 1968-02-15 1972-07-25 Organon Nv Process for the manufacture of rapidly disintegrating solid dosage unit forms

Cited By (17)

* Cited by examiner, † Cited by third party
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US4507276A (en) * 1982-08-20 1985-03-26 Bristol-Myers Company Analgesic capsule
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EP1713498A4 (en) * 2004-02-09 2009-07-15 Transfert Plus Sec COMPOSITION CONTAINING POLYMERIC MATERIAL AND USES THEREOF
US20190282519A1 (en) * 2018-03-19 2019-09-19 Cronus Research Labs Private Limited Pencillamine oral composition

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