CA1109796A - Process for the production of novel antidiarrheal agents - Google Patents
Process for the production of novel antidiarrheal agentsInfo
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- CA1109796A CA1109796A CA294,379A CA294379A CA1109796A CA 1109796 A CA1109796 A CA 1109796A CA 294379 A CA294379 A CA 294379A CA 1109796 A CA1109796 A CA 1109796A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/33—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans derived from pro-opiomelanocortin, pro-enkephalin or pro-dynorphin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/12—Antidiarrhoeals
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Abstract
PROCESS FOR THE PRODUCTION OF NOVEL ANTIDIARRHEAL AGENTS
Abstract of the Disclosure Medicaments for enteral administration which contain analgesic peptides of the endorphine type are potent anti-diarrheal agents causing minimum side-effects. Especially advantageous preparations are those containing leucine-encephaline or methionine-encephaline, in particular those formulated as coated tablets or tablets with an outer coat-ing which is resistant to solution in gastric fluid, an enteric coating for rapid release of the active ingredient, and a core for delayed release of the active ingredient.
Abstract of the Disclosure Medicaments for enteral administration which contain analgesic peptides of the endorphine type are potent anti-diarrheal agents causing minimum side-effects. Especially advantageous preparations are those containing leucine-encephaline or methionine-encephaline, in particular those formulated as coated tablets or tablets with an outer coat-ing which is resistant to solution in gastric fluid, an enteric coating for rapid release of the active ingredient, and a core for delayed release of the active ingredient.
Description
1~9t796 The present invention relates to a pharmaceutical preparation for enteral administration which contains as active ingredient 0,05 to 40% of one or more analgesic peptides of the endorphine type, in combination or admixture with at least one inert physiologically tolerable carrier and/or adjunct.
This preparation can be used for medically treating diarrheal conditions in mammals and especially in man by enteral adminl-stration of a pharmacolo~ically e~fective ~ose thereof.
It is generally known that analgesics of the nar-cotic type, such as opiates, diphenoxylate and loperamide, exert a strong inhibiting effect on the peristalsis and can therefore be used as effective antidiarrheal agents. In all probability, the inhibiting effect on the peristalsis is causally connected with the analgesic action. Peptides of the endorphine type are known to belong to the most potent analgesics of the narcotic type, but only on condition that they are administered by the intraventricular route. When administered intraperitoneally, on the other hand, the analgesic action is greatly reduced, and no activity has been observed on enteral, for example oral, administration. From this observation the conclusion was drawn that, on enteral administration, the endorphine peptides are also unable to exert any antidiarrheal effect and consequently are ruled out for practical use in therapy on account of the ' 11~9796 complicated and risky mode of administration.
However, the surprising discovery has now been made that the endorphine peptides are able to inhibit the peristalsis when administered enterally and have complete antidiarrheal properties, viz. under conditions in which their analgesic action is ineffective. The antidiarrheal agents on which this unexpected observation is based have the intrinsic advantage, compared with the other known analgesics of the narcotic type which exert an antidiarrheal effect, such as those mentioned above, that their active ingredients, i.e. the peptides of the endorphine type, are fragments of endogenic hormones or closely related analogues of such fragments. As such, they are to be regarded as physiological with respect to the metabolism and can be easily and completely decomposed by the metabolism in the body, in every likelihood already in the lumen of the bowels. Consequently they are able to exert their normalising action on the peristalsis without giving rise to the customary unpleasant symptoms of overdosage - for example an often prolonged constipation or even the danger of habituation and increasing the dose - which are well known to occur, especially with opiates. In contrast to the endorphine peptides, all other known antidiarrheal agents of the type discussed here have the draw~ack that they cannot be rapidly and completely decomposed by metabolic processes, but have to be much more slowly and partially modified before they attain a form in which they can be excreted from the organism.
_ 3 -37~36 Accordingly, the invention provides pharmaceutical preparations for enteral administration which exert an anti-diarrheal effect and ~hich contain, as active ingredients, one or more analgesic peptides of the endorphine type.
Enteral administration is to be understood as meaning in particular oral, and also rectal, administration.
By peptides of the endorphine type are meant ~-lipotropine fragments which are characterised by the amino acid partial sequence from the 61st amino acid up to and in-cluding at least the 65th and not more than the 91st amino acid, as well as derivatives and analogues thereof. Particularly advantageous compounds of this kind are the ~-lipo~ropine fragments 61-67 and 61-66. Compounds to be singled out for special mention however are the encephalines characterised by (i.e. the leucine-encephaline the pentapeptide fragment 61-65~of the formula H-Tyr-Gly-Gly-Phe-Leu-~H and, in particular, the methionine-encephaline of the formula H-Tyr-Gly-Gly-Phe-Met-OH. By analogues are meant compounds which are modified by the exchange of an amino acid of the original sequence for another amino acid, for example D-Ala2-Met5-encephaline and encephalines in which the leucine-radical is rep]aced by the L-valine, L-norvaline, L-iso-leucine, L-norleucine or L-~-aminobutyric acid radical. All these peptides can be in the free form or in the form of cor-responding derivatives, for example salts, in particular acid addition salts, or C-terminal amides Suitable acid components of the acid addition salts are pharmaceutically acceptable in-1~9796 organic and or~anic acids, for example hydrohalic acids, suchas hydrobromic acid and especially hydrochloric acid, sul-phuric acid, and phosphoric acids, as well as organic carboxy-lic or sulphonic acids, such as aliphatic, alicyclic, aromatic or heterocyclic carbo~ylic or sulphonic acids, for example formic, acetic, propionic, palmitic, stearic, succinic, glyco-lic, lactic, malic, tartaric, citric, ascorbic, pyruvic, phenylacetic, benzoic, p-hydroxybenzoic, salicylic, p-amino-salicylic, methanesulphonic, ethanesulphonic, hydroxyethane-sulphonic, ethylene-1,2-disulphonic, benzenesulphonic, toluene-- sulphonic or sulphanilic acid - ~he peptidic active ingredients are known or they can be prepared by conventional methods of peptide synthesis.
The preparations of the present invention contain the above active ingredients preferably in combination or admix-ture with the usual organic and/or inorganic solid or liquid carriers and adjuncts which are physiologically tolerable, inert to the active ingredient, and otherwise also suitable for each individual desired enteral form of administration.
Preparations in solid form are preferred. The preparations can contain in addition other therapeutically active substances of the same or different kind.
The preparations of the present in~ention are prefer-ably in dosage unit form. For administration to an adult, the preparation will contain from about 0.5 to about 100 mg of active ingredient or ingredients per dosage unit. The specific individual dose depends primarily on the pharmacological potency of each individual active ingredient and is, for ex-ample for leucine-encephaline, in the range from about 5 to about 100 mg, preferably from about 20 to 50 mg, and for methionine-encephaline, in the range from about 0.5 to about 10 mg 3 preferably from about 2 to ~ mg. For other suitable analogous peptides, the relative optimum individual dose can be determined by routine pharmacological tests. It will be readily understood that, in preparations for special use, for example for children or mammals, the individual dose must be adapted in accordance with the body weight of the specific re-cipient. For this purpose it is also possible to use tablcts with breaking notch.
The pharmaceutical preparations of the present inven-tion are obtained in a manner known per se, for example by ~onventional mixing, granulating, coating and/or solution methods. Accordingly, they can be obtained for example by com-bining the active ingredients with solid carriers, optionally granulating the resulting mixture and processing the mixture or granules, if desired or necessary after the addition of suitable adjuncts J to the desired form of administration.
Suitable preparations for rectal administration are for example solutions for enema infusion and, in particular, sup-positories and gelatin rectal capsules.
The solutions for enema application are preferably aqueous solutions which are prepared immediately before ad-ministration by dissolving a solid dosage unit form, preferablya tablet, in water of body temperature. Advantageously, such solid preparations contain all essential constituents in a water-soluble form, for example the active ingredient of the inven-tion as an acid addition salt, such as the hydrochloride. Other suitable constituents are especially the conventional hydro-tropic agents, disintegrators, buffers and compounds for alter-ing the osmotic pressure. Suitable methods of production are the conventional tabletting methods.
Particularly preferred dosage forms for rectal adminis-tration are suppositories, which consist in principle of a combination of the active ingredients with a suppository base.
Examples of suitable suppositor~ bases are natural or synthetic triglycerides, paraffin hydrocarbons, polyethylene glycols or higher alkanols. It is furthermore also possible to use gelatin rectal capsules which consist of a combination of the active ingredients with a base material. Examples of suitable base materials are liquid triglycerides and polyethylene glycols.
Particularly preferred dosage unit forms are solid pre-parations for oral administration, such as table~s, sugar-coated tablets and capsules. Particularly advantageous prepara-tions of this kind are in turn those dosage forms which resist solution in gastric fluid and are able to transport the active ingredient or ingredients through the alimentary tract into the small intestine intact, and, among such preparations, especially those in which a portion of the active ingrediPnt is released slowly and continuously over a prolonged period of time, for example from 2 to 8 and preferably 4 to 6 hours. Such parti-cularly preferred pharmaceutical forms of administration are for example tablets or sugar-coated tablets which contain an inner core consisting of a mixture for slow continuous release of the active ingredient (slow or delayed-release composition).
Surrounding this core is an enteric coating consisting of a mixture which releases the active ingredient instantly and which is provided in turn with an external coating which resists solution in gastric fluid but dissolves in the intestine.
Suitable carriers for solid preparations for oral ad-ministration are in particular fillers, such as sugar, for ex-ample, lactose, saccharose~ mannitol or sorbitol, cellulose preparations and/or calcium phosphates, e.g. tricalcium phos-phate or calcium hydrogen phosphate, also binders such as starch pastes, for example maize, corn, rice or potato starch paste, gelatin, tragacanth, methyl cellulose, hydroxypropyl-methylcellulose, sodium carboxymethylcellulose and/or poly-vinylpyrrolidone, and/or, if desired, disintegrators, such as the above starches, also carboxymethyl starch, crosslinked polyvinylpyrrolidone, agar, alginic acid or a salt thereof, such as sodium alginate. Adjuncts are chiefly glidants and lubricants, for example, silicic acid, talc, stearic acid or salts thereof, such as magnesium stearate or calcium stearate, and/or polyethylene glycol. Sugar-coated tablets cores are provided with suitable coatings that can be resistant to 1~9796 gastric juices, using, inter alia, concentrated sugar solu-tions which may contain gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, shellac solutions in suitable organic solvents or solvent mixtures or, for the preparation of coatings resistant to gastric juices, solutions of suitable cellulose preparations, such as acetylcellulose phthalate or hydroxypropylmethylcellulose phthalate. The duration of effect of an intrinsically short-acting active in-gredient can be prolonged for example by incorporating it in a suitable carrier which effects its slow release, as described in detail hereinafter. Dyes or pigments can be added to the tablets or sugar-coated tablet cores, for example to identify or indicate different doses of active ingredient.
Further pharmaceutical preparations for oral administra-tion are dry-filled capsules, and also soft sealed capsules made from gelatin and a plasticiser, such as glycerin or sorbitol. The dry-filled capsules can contain the active in-gredient in the form of granules, for example of those des-cribed in more detail hereinafter. In soft capsules, the active ingredient is preferably dissolved or suspended in suitable liquids, for example in fatty oils, paraffin oil or liquid polyethylene glycols, to which stabilisers can also be added.
A particularly advantageous form of the active in-gredient/carrier mixture are granulates which are suit-able for processing to tablets, sugar-coated tablets or cap-sules. In addition to the active ingredient, such granulates _ g _ 11~9796 contain, inter alia, diluents or fillers, such as sugar, for example lactose or saccharose, or sugar alcohols, for example mannitol or sorbitol, cellulose preparations and/or calcium phosphates, for example tricalcium phosphate or calcium hydro-gen phosphate, as well as glidants, such as talc or colloidal silicic acid, lubricants, such as stearic acid or salts ~here-of, for example magnesium or calcium stearate, and/or poly-ethylene glycol, and also glycerides, such as hydrogenated cot-ton seed or castor oil.
Granulates of this kind can be prepared in a manner which is known per se, with or without the use of moistening agents, such as water or organic solvents, for example ethanol, or mixtures thereof.
So that the release of the active ingredient is retarded and yet remains constant, it must be reduced by addition of and/or treatment with suitable adjuncts, excipients and/or coating substances. Such substances are in particular film formers for coatings, swelling substances with gel-forming properties for retarding the diffusion, builders for embed-dings, in particular lipids, and plastics with thermoplastic properties.
To achieve the delayed and continuous release of the active ingredient, only one adjunct of the above kind is nor-mally used.
Usually water-insoluble adjuncts are used in particular as film formers, for example water-insoluble cellulose ethers 9~796 or esters, such as corresponding cellulose lower alkyl ethers, for example water-insoluble ethyl cellulose, or water-insoluble cellulose esters containing hydroxyl groups which are esteri-fied by lower alkanecarboxylic acids or dicarboxylic acids, for example water-insoluble cellulose acetate or cellulose acetate phthalate, polymers or copolymers of unsaturated aliphatic esters of carboxylic acids with alcohols, such as polymers or copolymers of esters of lower alkene-carboxylic acids with lower alkanols, for example copolymers of ethyl acrylate and methyl methacrylate (e.g. in the ratio of about 70 parts of ethyl acrylate to about 30 parts of methyl methacrylate), and shellac.
The film formers, which comprise between about 1% and 10%, preferably between about 2% and 6%, of the total weight of the preparation formulation, are used chiefly for coating active ingredient particles or preferably of granulates, or also as additive to granulates, which can be compressed to tablets. -They can be applied or admixed in dissolved form using organic solvents, for example alcohols, such as ethanol, or optionally chlorinated aliphatic hydrocarbons, such as methylene chloride, or ketones, for example acetone, or mixtures thereof, or in the form of dispersions, such as coagulatable a~ueous dispersions.
Suitable swelling substances are in particular ethers of cellulose which have a high degree of viscosity, such as corresponding lower alkyl celluloses and in particular methyl cellulose with an average degree of substitution of about 1.8, and which are added preferably in powder form to the active 1~9~96 ingredient or especially to granulates thereof. The resultant mixtures are then processed for example to tablets. By this means there are obtained pharmaceutical preparations which, on contact with water, swell with gel formation, resulting in the formation of a diffusion barrier which is independent of the pH.
Lipids which are suitable water-insoluble builders are, inter alia, fatty alcohols, in particular higher alkanols of more than 13, in particular of 16 to 20, carbon atoms, for ex-ample cetyl alcohol or stearyl alcohol, and mixtures thereof.
These lipids can be used for the release of the active ingre-dient which is independent of the pH. Further suitable lipids are fatty acids which effect a release of the active ingredient that is dependent of the pH, in particular higher alkane-carboxylic acids of more than 13, in particular of 16 to 20, carbon atoms, for example stearic acid. Such lipids can be used in powder or in fused form. Suitable lipids are also glycerides, in particular hydrogenated vegetable oils, such as hydrogenated vegetable oils, such as hydrogenated cotton seed oil or hydro-genated castor oil, as well as mono-, di- or triesters of gly-cerol with palmitic acid or stearic acid or preferably mix-tures thereof. These lipids are normally used in powder form and can be employed simultaneously, as mentioned above, as glidants.
Plastics with thermoplastic properties which can be used as water-insoluble builders are in particular polymers or copolymers of the polyvinyl chloride or polyvinyl acetate type.
, :
The swelling substances and builders which are used in amounts of about 5% to about 70%, preferably of about 10% to about 40%, of the total weight of the preparation, are usually mixed with the active ingredient or preferably with an active ingredient/adjunct mixture, such as a granulated mixture, and, if appropriate after the addition of further adjuncts, such as glidants and lubricants, compressed to tablets or capsules.
It is a further object of the present invention to provide a method of treating mammals, and especially man, to alleviate and overcome diarrheal conditions by the enteral ad-ministration of therapeutically effective doses of the anal-gesic peptides of the endorphine type, espe~ially of those specifically referred to herein, which comprises administering the active ingredients, advantageously in the form of the above described pharmaceutical preparations, in the indicated general or specific individual doses and in the manner as des-cribed above. Depending on the nature of the symptoms and the form of administration, as well as according to individual re~uirements, the individual doses can be taken once or repeat-edly. As a rule, the total dosage shall not exceed 10 indi-vidual doses in the course of 24 hours.
The following Examples illustrate the invention but do not in any way restrict the scope thereof.
.
Example 1 Film-coated tablets which resist solution in gastric fluid but disintegrate in the intestine, for combined rapid and slow release of the active ingredient.
Using conventional mixing methods, homogeneous mixtures of the following composition are prepared:
Mixture A
leucine-encephaline 100 g lactose, anhydrous, for direct 950 g tabletting cellulose, microcrystalline 650 g magnesium stearate 10 g Mixture B
leucine-encephaline 150 g lactose, microcrystalline, for direct 400 g tabletting hydrogenated castor oil, fine-grained 50 g Mixtures A and B are compressed to enteric-coated tablets.
Mixture B is first compressed to the core with prolonged action which weighs 60 mg and has a diameter of 6 mm. The enteric-coating with rapid release of~the active ingredient is pre-pared from mixture A in an amount of 171 mg. Slightly domed punches having a diameter of 8 mm are used, so that enteric-coated tablets having a total weight of 231 mg and containing 10 mg of the active ingredient in rapid-acting form and 15 mg in the slow-release form are obtained.
)9~96 The enteric-coated tablets in batches of 100,000 are coated in a coating drum o~ 65 cm diameter by means of automatic spray equipment with a shellac solution of the following composition:
methylene chloride 18.2 kg methanol 1.42 kg cellulose acetate phthalate0.662 kg diethyl phthalate 0.207 kg shellac 0.211 kg The temperature of the supply air is 60C and the temperature of the cores is kept at about 25C. The finished film-coated tablets are subsequently dried for 12 hours at 30C.
~ xample 2 Film-coated tablets which resist solution in gastric fluid and disintegrate in the intestine for combined rapid and slow release of the active ingredient are prepared in a manner analogous to that described in Example 1. The tablets have a total content of 10 mg of methionine-encephaline, viz. 4 mg in the rapid-acting form and 6 mg in the slow-release form.
The mixtures required for preparing the tablets have the fol-lowing composition:
Mixture A
methionine-encephaline 40 g lactose, anhydrous, for direct1000 g tabletting ~ 7 ~ 6 cellulose, microcrystalline 660 g magnesium stearate 10 g Mixture B
methionine-encephaline 60 g lactose, anhydrous, for direct 490 g tabletting hydrogenated castor oil, fine-grained 50 g Processing is carried out under the conditions indicated in Example l.
Example 3 Dry-filled capsules which resist solution in gastric fluid and disintegrate in the intestine.
A mixture of the following composition is prepared:
leucine-encephaline 500 g maize starch 300 g lactose, crystalline with an average 400 g particle size of about 125 ,u lactose, finely ground 200 g calcium stearate 50 g Size 2 hard gelatin capsules, which during the capsule manu-facturing process have been made resistant to solution in gastric fluid by being dipped in an organic solution of hydroxy-propylmethylcellulose (type ~P 55), are each filled with 145 mg of this mixture. The finished capsules contain 50 mg of active ingredient.
`\
Example 4 Dry-filled capsules containing a total amount of 5 mg of methionine-encephaline and which are resistant to solution in gastric fluid and disintegrate in the intestine are prepared in a manner analogous to that of Example 3. The mixture re-quired for these capsules has the following composition:
methionine-encephaline 50 g maize starch 750 g lactose, crystalline (cf. Example 3) 400 g lactose, finely ground 200 g calcium stearate 50 g The processing is carried out under the conditions indicated i.n Example 3.
This preparation can be used for medically treating diarrheal conditions in mammals and especially in man by enteral adminl-stration of a pharmacolo~ically e~fective ~ose thereof.
It is generally known that analgesics of the nar-cotic type, such as opiates, diphenoxylate and loperamide, exert a strong inhibiting effect on the peristalsis and can therefore be used as effective antidiarrheal agents. In all probability, the inhibiting effect on the peristalsis is causally connected with the analgesic action. Peptides of the endorphine type are known to belong to the most potent analgesics of the narcotic type, but only on condition that they are administered by the intraventricular route. When administered intraperitoneally, on the other hand, the analgesic action is greatly reduced, and no activity has been observed on enteral, for example oral, administration. From this observation the conclusion was drawn that, on enteral administration, the endorphine peptides are also unable to exert any antidiarrheal effect and consequently are ruled out for practical use in therapy on account of the ' 11~9796 complicated and risky mode of administration.
However, the surprising discovery has now been made that the endorphine peptides are able to inhibit the peristalsis when administered enterally and have complete antidiarrheal properties, viz. under conditions in which their analgesic action is ineffective. The antidiarrheal agents on which this unexpected observation is based have the intrinsic advantage, compared with the other known analgesics of the narcotic type which exert an antidiarrheal effect, such as those mentioned above, that their active ingredients, i.e. the peptides of the endorphine type, are fragments of endogenic hormones or closely related analogues of such fragments. As such, they are to be regarded as physiological with respect to the metabolism and can be easily and completely decomposed by the metabolism in the body, in every likelihood already in the lumen of the bowels. Consequently they are able to exert their normalising action on the peristalsis without giving rise to the customary unpleasant symptoms of overdosage - for example an often prolonged constipation or even the danger of habituation and increasing the dose - which are well known to occur, especially with opiates. In contrast to the endorphine peptides, all other known antidiarrheal agents of the type discussed here have the draw~ack that they cannot be rapidly and completely decomposed by metabolic processes, but have to be much more slowly and partially modified before they attain a form in which they can be excreted from the organism.
_ 3 -37~36 Accordingly, the invention provides pharmaceutical preparations for enteral administration which exert an anti-diarrheal effect and ~hich contain, as active ingredients, one or more analgesic peptides of the endorphine type.
Enteral administration is to be understood as meaning in particular oral, and also rectal, administration.
By peptides of the endorphine type are meant ~-lipotropine fragments which are characterised by the amino acid partial sequence from the 61st amino acid up to and in-cluding at least the 65th and not more than the 91st amino acid, as well as derivatives and analogues thereof. Particularly advantageous compounds of this kind are the ~-lipo~ropine fragments 61-67 and 61-66. Compounds to be singled out for special mention however are the encephalines characterised by (i.e. the leucine-encephaline the pentapeptide fragment 61-65~of the formula H-Tyr-Gly-Gly-Phe-Leu-~H and, in particular, the methionine-encephaline of the formula H-Tyr-Gly-Gly-Phe-Met-OH. By analogues are meant compounds which are modified by the exchange of an amino acid of the original sequence for another amino acid, for example D-Ala2-Met5-encephaline and encephalines in which the leucine-radical is rep]aced by the L-valine, L-norvaline, L-iso-leucine, L-norleucine or L-~-aminobutyric acid radical. All these peptides can be in the free form or in the form of cor-responding derivatives, for example salts, in particular acid addition salts, or C-terminal amides Suitable acid components of the acid addition salts are pharmaceutically acceptable in-1~9796 organic and or~anic acids, for example hydrohalic acids, suchas hydrobromic acid and especially hydrochloric acid, sul-phuric acid, and phosphoric acids, as well as organic carboxy-lic or sulphonic acids, such as aliphatic, alicyclic, aromatic or heterocyclic carbo~ylic or sulphonic acids, for example formic, acetic, propionic, palmitic, stearic, succinic, glyco-lic, lactic, malic, tartaric, citric, ascorbic, pyruvic, phenylacetic, benzoic, p-hydroxybenzoic, salicylic, p-amino-salicylic, methanesulphonic, ethanesulphonic, hydroxyethane-sulphonic, ethylene-1,2-disulphonic, benzenesulphonic, toluene-- sulphonic or sulphanilic acid - ~he peptidic active ingredients are known or they can be prepared by conventional methods of peptide synthesis.
The preparations of the present invention contain the above active ingredients preferably in combination or admix-ture with the usual organic and/or inorganic solid or liquid carriers and adjuncts which are physiologically tolerable, inert to the active ingredient, and otherwise also suitable for each individual desired enteral form of administration.
Preparations in solid form are preferred. The preparations can contain in addition other therapeutically active substances of the same or different kind.
The preparations of the present in~ention are prefer-ably in dosage unit form. For administration to an adult, the preparation will contain from about 0.5 to about 100 mg of active ingredient or ingredients per dosage unit. The specific individual dose depends primarily on the pharmacological potency of each individual active ingredient and is, for ex-ample for leucine-encephaline, in the range from about 5 to about 100 mg, preferably from about 20 to 50 mg, and for methionine-encephaline, in the range from about 0.5 to about 10 mg 3 preferably from about 2 to ~ mg. For other suitable analogous peptides, the relative optimum individual dose can be determined by routine pharmacological tests. It will be readily understood that, in preparations for special use, for example for children or mammals, the individual dose must be adapted in accordance with the body weight of the specific re-cipient. For this purpose it is also possible to use tablcts with breaking notch.
The pharmaceutical preparations of the present inven-tion are obtained in a manner known per se, for example by ~onventional mixing, granulating, coating and/or solution methods. Accordingly, they can be obtained for example by com-bining the active ingredients with solid carriers, optionally granulating the resulting mixture and processing the mixture or granules, if desired or necessary after the addition of suitable adjuncts J to the desired form of administration.
Suitable preparations for rectal administration are for example solutions for enema infusion and, in particular, sup-positories and gelatin rectal capsules.
The solutions for enema application are preferably aqueous solutions which are prepared immediately before ad-ministration by dissolving a solid dosage unit form, preferablya tablet, in water of body temperature. Advantageously, such solid preparations contain all essential constituents in a water-soluble form, for example the active ingredient of the inven-tion as an acid addition salt, such as the hydrochloride. Other suitable constituents are especially the conventional hydro-tropic agents, disintegrators, buffers and compounds for alter-ing the osmotic pressure. Suitable methods of production are the conventional tabletting methods.
Particularly preferred dosage forms for rectal adminis-tration are suppositories, which consist in principle of a combination of the active ingredients with a suppository base.
Examples of suitable suppositor~ bases are natural or synthetic triglycerides, paraffin hydrocarbons, polyethylene glycols or higher alkanols. It is furthermore also possible to use gelatin rectal capsules which consist of a combination of the active ingredients with a base material. Examples of suitable base materials are liquid triglycerides and polyethylene glycols.
Particularly preferred dosage unit forms are solid pre-parations for oral administration, such as table~s, sugar-coated tablets and capsules. Particularly advantageous prepara-tions of this kind are in turn those dosage forms which resist solution in gastric fluid and are able to transport the active ingredient or ingredients through the alimentary tract into the small intestine intact, and, among such preparations, especially those in which a portion of the active ingrediPnt is released slowly and continuously over a prolonged period of time, for example from 2 to 8 and preferably 4 to 6 hours. Such parti-cularly preferred pharmaceutical forms of administration are for example tablets or sugar-coated tablets which contain an inner core consisting of a mixture for slow continuous release of the active ingredient (slow or delayed-release composition).
Surrounding this core is an enteric coating consisting of a mixture which releases the active ingredient instantly and which is provided in turn with an external coating which resists solution in gastric fluid but dissolves in the intestine.
Suitable carriers for solid preparations for oral ad-ministration are in particular fillers, such as sugar, for ex-ample, lactose, saccharose~ mannitol or sorbitol, cellulose preparations and/or calcium phosphates, e.g. tricalcium phos-phate or calcium hydrogen phosphate, also binders such as starch pastes, for example maize, corn, rice or potato starch paste, gelatin, tragacanth, methyl cellulose, hydroxypropyl-methylcellulose, sodium carboxymethylcellulose and/or poly-vinylpyrrolidone, and/or, if desired, disintegrators, such as the above starches, also carboxymethyl starch, crosslinked polyvinylpyrrolidone, agar, alginic acid or a salt thereof, such as sodium alginate. Adjuncts are chiefly glidants and lubricants, for example, silicic acid, talc, stearic acid or salts thereof, such as magnesium stearate or calcium stearate, and/or polyethylene glycol. Sugar-coated tablets cores are provided with suitable coatings that can be resistant to 1~9796 gastric juices, using, inter alia, concentrated sugar solu-tions which may contain gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, shellac solutions in suitable organic solvents or solvent mixtures or, for the preparation of coatings resistant to gastric juices, solutions of suitable cellulose preparations, such as acetylcellulose phthalate or hydroxypropylmethylcellulose phthalate. The duration of effect of an intrinsically short-acting active in-gredient can be prolonged for example by incorporating it in a suitable carrier which effects its slow release, as described in detail hereinafter. Dyes or pigments can be added to the tablets or sugar-coated tablet cores, for example to identify or indicate different doses of active ingredient.
Further pharmaceutical preparations for oral administra-tion are dry-filled capsules, and also soft sealed capsules made from gelatin and a plasticiser, such as glycerin or sorbitol. The dry-filled capsules can contain the active in-gredient in the form of granules, for example of those des-cribed in more detail hereinafter. In soft capsules, the active ingredient is preferably dissolved or suspended in suitable liquids, for example in fatty oils, paraffin oil or liquid polyethylene glycols, to which stabilisers can also be added.
A particularly advantageous form of the active in-gredient/carrier mixture are granulates which are suit-able for processing to tablets, sugar-coated tablets or cap-sules. In addition to the active ingredient, such granulates _ g _ 11~9796 contain, inter alia, diluents or fillers, such as sugar, for example lactose or saccharose, or sugar alcohols, for example mannitol or sorbitol, cellulose preparations and/or calcium phosphates, for example tricalcium phosphate or calcium hydro-gen phosphate, as well as glidants, such as talc or colloidal silicic acid, lubricants, such as stearic acid or salts ~here-of, for example magnesium or calcium stearate, and/or poly-ethylene glycol, and also glycerides, such as hydrogenated cot-ton seed or castor oil.
Granulates of this kind can be prepared in a manner which is known per se, with or without the use of moistening agents, such as water or organic solvents, for example ethanol, or mixtures thereof.
So that the release of the active ingredient is retarded and yet remains constant, it must be reduced by addition of and/or treatment with suitable adjuncts, excipients and/or coating substances. Such substances are in particular film formers for coatings, swelling substances with gel-forming properties for retarding the diffusion, builders for embed-dings, in particular lipids, and plastics with thermoplastic properties.
To achieve the delayed and continuous release of the active ingredient, only one adjunct of the above kind is nor-mally used.
Usually water-insoluble adjuncts are used in particular as film formers, for example water-insoluble cellulose ethers 9~796 or esters, such as corresponding cellulose lower alkyl ethers, for example water-insoluble ethyl cellulose, or water-insoluble cellulose esters containing hydroxyl groups which are esteri-fied by lower alkanecarboxylic acids or dicarboxylic acids, for example water-insoluble cellulose acetate or cellulose acetate phthalate, polymers or copolymers of unsaturated aliphatic esters of carboxylic acids with alcohols, such as polymers or copolymers of esters of lower alkene-carboxylic acids with lower alkanols, for example copolymers of ethyl acrylate and methyl methacrylate (e.g. in the ratio of about 70 parts of ethyl acrylate to about 30 parts of methyl methacrylate), and shellac.
The film formers, which comprise between about 1% and 10%, preferably between about 2% and 6%, of the total weight of the preparation formulation, are used chiefly for coating active ingredient particles or preferably of granulates, or also as additive to granulates, which can be compressed to tablets. -They can be applied or admixed in dissolved form using organic solvents, for example alcohols, such as ethanol, or optionally chlorinated aliphatic hydrocarbons, such as methylene chloride, or ketones, for example acetone, or mixtures thereof, or in the form of dispersions, such as coagulatable a~ueous dispersions.
Suitable swelling substances are in particular ethers of cellulose which have a high degree of viscosity, such as corresponding lower alkyl celluloses and in particular methyl cellulose with an average degree of substitution of about 1.8, and which are added preferably in powder form to the active 1~9~96 ingredient or especially to granulates thereof. The resultant mixtures are then processed for example to tablets. By this means there are obtained pharmaceutical preparations which, on contact with water, swell with gel formation, resulting in the formation of a diffusion barrier which is independent of the pH.
Lipids which are suitable water-insoluble builders are, inter alia, fatty alcohols, in particular higher alkanols of more than 13, in particular of 16 to 20, carbon atoms, for ex-ample cetyl alcohol or stearyl alcohol, and mixtures thereof.
These lipids can be used for the release of the active ingre-dient which is independent of the pH. Further suitable lipids are fatty acids which effect a release of the active ingredient that is dependent of the pH, in particular higher alkane-carboxylic acids of more than 13, in particular of 16 to 20, carbon atoms, for example stearic acid. Such lipids can be used in powder or in fused form. Suitable lipids are also glycerides, in particular hydrogenated vegetable oils, such as hydrogenated vegetable oils, such as hydrogenated cotton seed oil or hydro-genated castor oil, as well as mono-, di- or triesters of gly-cerol with palmitic acid or stearic acid or preferably mix-tures thereof. These lipids are normally used in powder form and can be employed simultaneously, as mentioned above, as glidants.
Plastics with thermoplastic properties which can be used as water-insoluble builders are in particular polymers or copolymers of the polyvinyl chloride or polyvinyl acetate type.
, :
The swelling substances and builders which are used in amounts of about 5% to about 70%, preferably of about 10% to about 40%, of the total weight of the preparation, are usually mixed with the active ingredient or preferably with an active ingredient/adjunct mixture, such as a granulated mixture, and, if appropriate after the addition of further adjuncts, such as glidants and lubricants, compressed to tablets or capsules.
It is a further object of the present invention to provide a method of treating mammals, and especially man, to alleviate and overcome diarrheal conditions by the enteral ad-ministration of therapeutically effective doses of the anal-gesic peptides of the endorphine type, espe~ially of those specifically referred to herein, which comprises administering the active ingredients, advantageously in the form of the above described pharmaceutical preparations, in the indicated general or specific individual doses and in the manner as des-cribed above. Depending on the nature of the symptoms and the form of administration, as well as according to individual re~uirements, the individual doses can be taken once or repeat-edly. As a rule, the total dosage shall not exceed 10 indi-vidual doses in the course of 24 hours.
The following Examples illustrate the invention but do not in any way restrict the scope thereof.
.
Example 1 Film-coated tablets which resist solution in gastric fluid but disintegrate in the intestine, for combined rapid and slow release of the active ingredient.
Using conventional mixing methods, homogeneous mixtures of the following composition are prepared:
Mixture A
leucine-encephaline 100 g lactose, anhydrous, for direct 950 g tabletting cellulose, microcrystalline 650 g magnesium stearate 10 g Mixture B
leucine-encephaline 150 g lactose, microcrystalline, for direct 400 g tabletting hydrogenated castor oil, fine-grained 50 g Mixtures A and B are compressed to enteric-coated tablets.
Mixture B is first compressed to the core with prolonged action which weighs 60 mg and has a diameter of 6 mm. The enteric-coating with rapid release of~the active ingredient is pre-pared from mixture A in an amount of 171 mg. Slightly domed punches having a diameter of 8 mm are used, so that enteric-coated tablets having a total weight of 231 mg and containing 10 mg of the active ingredient in rapid-acting form and 15 mg in the slow-release form are obtained.
)9~96 The enteric-coated tablets in batches of 100,000 are coated in a coating drum o~ 65 cm diameter by means of automatic spray equipment with a shellac solution of the following composition:
methylene chloride 18.2 kg methanol 1.42 kg cellulose acetate phthalate0.662 kg diethyl phthalate 0.207 kg shellac 0.211 kg The temperature of the supply air is 60C and the temperature of the cores is kept at about 25C. The finished film-coated tablets are subsequently dried for 12 hours at 30C.
~ xample 2 Film-coated tablets which resist solution in gastric fluid and disintegrate in the intestine for combined rapid and slow release of the active ingredient are prepared in a manner analogous to that described in Example 1. The tablets have a total content of 10 mg of methionine-encephaline, viz. 4 mg in the rapid-acting form and 6 mg in the slow-release form.
The mixtures required for preparing the tablets have the fol-lowing composition:
Mixture A
methionine-encephaline 40 g lactose, anhydrous, for direct1000 g tabletting ~ 7 ~ 6 cellulose, microcrystalline 660 g magnesium stearate 10 g Mixture B
methionine-encephaline 60 g lactose, anhydrous, for direct 490 g tabletting hydrogenated castor oil, fine-grained 50 g Processing is carried out under the conditions indicated in Example l.
Example 3 Dry-filled capsules which resist solution in gastric fluid and disintegrate in the intestine.
A mixture of the following composition is prepared:
leucine-encephaline 500 g maize starch 300 g lactose, crystalline with an average 400 g particle size of about 125 ,u lactose, finely ground 200 g calcium stearate 50 g Size 2 hard gelatin capsules, which during the capsule manu-facturing process have been made resistant to solution in gastric fluid by being dipped in an organic solution of hydroxy-propylmethylcellulose (type ~P 55), are each filled with 145 mg of this mixture. The finished capsules contain 50 mg of active ingredient.
`\
Example 4 Dry-filled capsules containing a total amount of 5 mg of methionine-encephaline and which are resistant to solution in gastric fluid and disintegrate in the intestine are prepared in a manner analogous to that of Example 3. The mixture re-quired for these capsules has the following composition:
methionine-encephaline 50 g maize starch 750 g lactose, crystalline (cf. Example 3) 400 g lactose, finely ground 200 g calcium stearate 50 g The processing is carried out under the conditions indicated i.n Example 3.
Claims (20)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A pharmaceutical preparation for enteral adminis-tration which contains as active ingredient 0,05 to 40 %
of one or more analgesic peptides of the endorphine type in combination or admixture with at least one inert phy-siologically tolerable carrier and/or adjunct.
of one or more analgesic peptides of the endorphine type in combination or admixture with at least one inert phy-siologically tolerable carrier and/or adjunct.
2. A pharmaceutical preparation as claimed in claim 1 which contains as active ingredient one or more peptides having a .beta.-lipotropine partial sequence from the 61st amino acid up to and including at least the 65th and not higher than the 91st amino acid or the analogues thereof, wherein one of the amino acids of the original sequence is exchanged for another amino acid,or a derivative there-of.
3. A pharmaceutical preparation as claimed in claim 2 which contains as active ingredient a pentapeptide charac-terised by the amino acid partial sequence 61-65, wherein one of the original amino acids can be exchanged for ano-ther amino acid, or an acid addition salt or C-terminal amide thereof.
4. A pharmaceutical preparation as claimed in claim 3 which contains as active ingredient leucine-encephaline of the formula H-Tyr-Gly-Gly-Phe-Leu-OH
or an acid addition salt or C-terminal amide thereof.
or an acid addition salt or C-terminal amide thereof.
5. A pharmaceutical preparation as claimed in claim 3 which contains as active ingredient methionine-encephaline of the formula H-Tyr-Gly-Gly-Phe-Met-OH
or an acid addition salt or C-terminal amide thereof.
or an acid addition salt or C-terminal amide thereof.
6. A pharmaceutical preparation as claimed in any one of claims 2, 4 and 5 in the form of dosage units.
7. A pharmaceutical preparation as claimed in claim 1 for oral administration.
8. A pharmaceutical preparation as claimed in any one of claims 2 to 4 for oral administration.
9. A pharmaceutical preparation as claimed in claim 1 for rectal administration.
10. A pharmaceutical preparation as claimed in any one of claims 2 to 4 for rectal administration.
11. A pharmaceutical preparation as claimed in claim 1, in the form of tablets or capsules, which are resistant to solution in gastric fluid and disintegrate in the intestine.
12. A pharmaceutical preparation as claimed in any one of claims 3, 7 and 9 in the form of tablets, coated tablets or capsules, which are resistant to solution in gastric fluid and disintegrate in the intestine.
13. A pharmaceutical preparation as claimed in claim 11 which consists of a core for slow release of the active ingredient, an enteric-coating for rapid release of the active ingredient and an outer coating which is resistant to solution in gastric fluid and dissolves in the intes-tine.
14. A pharmaceutical preparation as claimed in any one of claims 7, 9 and 13 wherein the content of an active ingredient, or the total content of several such active ingredients, is from about 0.5 to about 100 mg per dosage unit for administration to adults.
15. A pharmaceutical preparation as claimed in any one of claims 7, 9 and 13 wherein the content of leucine-encephaline is from about 5 to about 100 mg per dosage unit for administration to adults.
16. A pharmaceutical preparation as claimed in claim 4 wherein the content of leucine-encephaline is from about 5 to about 100 mg per dosage unit for administration to adults.
17. A pharmaceutical preparation as claimed in claim 16 wherein the content of leucine-encephaline is about 20 to 50 mg per dosage unit for administration to adults.
18. A pharmaceutical preparation as claimed in claim 5 wherein the content of methionine-encephaline is from about 0.5 to about 10 mg per dosage unit for administra-tion to adults.
19. A pharmaceutical preparation as claimed in any one of claims 7, 9 and 13, wherein the content of methionine-encephaline is from about 0.5 to about 10 mg per dosage unit for administration to adults.
20. A pharmaceutical preparation as claimed in any one of claims 7, 9 and 13 wherein the content of methionine-encephaline is about 2 to 5 mg per dosage unit for adminis-tration to adults.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| LU76538A LU76538A1 (en) | 1977-01-07 | 1977-01-07 | |
| LU76538 | 1977-01-07 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1109796A true CA1109796A (en) | 1981-09-29 |
Family
ID=19728442
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA294,379A Expired CA1109796A (en) | 1977-01-07 | 1978-01-05 | Process for the production of novel antidiarrheal agents |
Country Status (13)
| Country | Link |
|---|---|
| JP (1) | JPS5388332A (en) |
| AU (1) | AU3221778A (en) |
| BE (1) | BE862689A (en) |
| CA (1) | CA1109796A (en) |
| DE (1) | DE2800110A1 (en) |
| FR (1) | FR2376663A1 (en) |
| GB (1) | GB1595021A (en) |
| IE (1) | IE46241B1 (en) |
| IL (1) | IL53760A (en) |
| IT (1) | IT7847545A0 (en) |
| LU (1) | LU76538A1 (en) |
| NL (1) | NL7800045A (en) |
| ZA (1) | ZA7887B (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5783193A (en) * | 1991-06-21 | 1998-07-21 | The University Of Cincinnati | Oral administration of therapeutic proteins for treatment of autoimmune disease, transplant rejection and infectious disease |
| US6613332B1 (en) | 1991-06-21 | 2003-09-02 | The University Of Cincinnati | Oral administration of therapeutic proteins |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4668517A (en) * | 1985-04-04 | 1987-05-26 | Norwich Eaton Pharmaceuticals, Inc. | Furazolidone dosage form |
| NL8503413A (en) * | 1985-12-11 | 1987-07-01 | Vereniging Voor Christelijk Wetenschappelijk Onderwijs | PREPARATIONS FOR THE PREVENTION OF DIARRHEE. |
-
1977
- 1977-01-07 LU LU76538A patent/LU76538A1/xx unknown
-
1978
- 1978-01-02 NL NL7800045A patent/NL7800045A/en not_active Application Discontinuation
- 1978-01-03 DE DE19782800110 patent/DE2800110A1/en not_active Withdrawn
- 1978-01-05 GB GB340/78A patent/GB1595021A/en not_active Expired
- 1978-01-05 CA CA294,379A patent/CA1109796A/en not_active Expired
- 1978-01-05 FR FR7800206A patent/FR2376663A1/en active Granted
- 1978-01-06 AU AU32217/78A patent/AU3221778A/en active Pending
- 1978-01-06 IL IL53760A patent/IL53760A/en unknown
- 1978-01-06 BE BE184140A patent/BE862689A/en unknown
- 1978-01-06 IE IE32/78A patent/IE46241B1/en unknown
- 1978-01-06 IT IT7847545A patent/IT7847545A0/en unknown
- 1978-01-06 ZA ZA00780087A patent/ZA7887B/en unknown
- 1978-01-07 JP JP39678A patent/JPS5388332A/en active Pending
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5783193A (en) * | 1991-06-21 | 1998-07-21 | The University Of Cincinnati | Oral administration of therapeutic proteins for treatment of autoimmune disease, transplant rejection and infectious disease |
| US6174529B1 (en) | 1991-06-21 | 2001-01-16 | University Of Cincinnati | Oral therapy for the treatment of allergies and method of manufacture |
| US6613332B1 (en) | 1991-06-21 | 2003-09-02 | The University Of Cincinnati | Oral administration of therapeutic proteins |
Also Published As
| Publication number | Publication date |
|---|---|
| IL53760A0 (en) | 1978-04-30 |
| IT7847545A0 (en) | 1978-01-06 |
| IE46241B1 (en) | 1983-04-06 |
| IE780032L (en) | 1978-07-07 |
| LU76538A1 (en) | 1978-09-18 |
| GB1595021A (en) | 1981-08-05 |
| JPS5388332A (en) | 1978-08-03 |
| AU3221778A (en) | 1979-07-12 |
| FR2376663B1 (en) | 1981-11-20 |
| DE2800110A1 (en) | 1978-07-13 |
| FR2376663A1 (en) | 1978-08-04 |
| BE862689A (en) | 1978-07-06 |
| ZA7887B (en) | 1978-11-29 |
| NL7800045A (en) | 1978-07-11 |
| IL53760A (en) | 1981-07-31 |
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