IE46241B1 - Process for the preparation of antidiarrheal agents - Google Patents

Abstract

PROCESS FOR THE PRODUCTION OF NOVEL ANTIDIARRHEAL AGENTS Medicaments for enteral administration which contain analgesic peptides of the endorphine type are potent antidiarrheal agents causing minimum side-effects. Especially advantageous preparations are those containing leucineencephaline or methionine-encephaline, in particular those formulated as coated tablets or tablets with an outer coating 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

The present invention relates to pharmaceutical preparations for enteral administration which contain as pharmaceutical active ingredient, one or more analgesic peptides of the endorphine type, as well as to a process for obtaining said preparations and to their use in the treatment of diarrheal conditions in mammals and especially in man. The invention also relates to a method of medically treating diarrheal conditions in mammals and especially in man by the enteral administration of a pharmacologically effective dose of one or more analgesic1 peptides of the endorphine type, preferably in the form of a suitable pharmaceutical preparation.

It is generally known that analgesics of the narcotic type, such as opiates, diphenoxylate and loperamide, exert a strong inhibiting effect on peristalsis and can therefore be used as effective antidiarrheal agents. In all probability, the inhibiting effect on 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 the condition that they are administered by the intraventricular route.

When administered1 intraperitoneally, on the other hand, the analgesic action is greatly reduced, and no activity has been observed on enteral, for example oral, administration. Prom 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 complicated and risky mode of administration.

However, the surprising discovery has now been made that the endorphine peptides are able to inhibit 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 even in the lumen of the bowels. Consequently they are able to exert their normalising action on 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 draw25 back 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.

Accordingly, the invention provides pharmaceutical preparations for enteral administration which exert an antidiarrheal effect and which contain, as active 6 2 41 - 4 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 ’ βlipotropine fragments which are characterised by the amino acid partial sequence from the 61st amino acid up to and including at least the 65th and not more than the 91st amino acid, as well as derivatives and analogous thereof.

Particularly advantageous compounds of this kind are the βlipotropine fragments 61-67 and 61-66. Compounds to be singled out for special mention however are the encephalines characterised by the pentapeptide fragment 61-65, i.e. the leucine-encephaline, of the formula H-Tyr-Gly-Gly-Phe-Leu-OH and, in particular, the methionine-encephaline of the formula H-Tyr-Gly-Gly-Phe-Mat-OH. By analogues are meant compounds which are modified by the exchange of an amino acid of the . 2 original sequence for another ammo acid, for example D-Ala 5 Met -encephaline in which the leucine-5 radical is replaced by an L-valine, L-norvaline, L-isoleucine, L-norleucine or L-a-aminobutyric acid radical. All the peptides of the endorphin type can be in the free form or in the form of a corresponding derivative, for example a salt, in particular an acid addition salt, or a c-terminal amide. An acid component of an acid, addition salt is for example, a pharmaceutically acceptable inorganic or organic acid, for example a hydrohalic acid for example, hydrobromic acid or especially hydrochloric acid, sulphuric acid, or a phosphoric acid, or an organic carboxylic or sulphonic acid for example, an aliphatic, alicyclic, aromatic or heterocyclic carboxylic - 5 or sulphonic acid, for example formic, acetic, propionic, palmitic, stearic, succinic, glycolic, lactic, malic, tartaric, citric, ascorbic, pyruvic, phenylacetic, benzoic, p-hydroxybenzoic, salicylic, p-aminosalicylic, methanesulphonic, ethanesulphonic, hydroxyethanesulphonic, ethylene1.2-disulphonic, benzenesulphonic, toluenesulphonic or sulphanilic acid.

The peptidic active ingredients are known or they can be prepared by conventional methods of peptide synthesis.

The preparations of the present invention comprise the above active ingredients preferably in conjunction or admixture 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 a different kind.

The preparations of the present invention are preferably in dosage unit form. For administration to an adult, the preparation will generally contain from 0.5 to 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 example for leucine-encephaline, in the range from 5 to 100 mg, preferably from 20 to 50 mg, and for methionineenoephaline, in the range from 0.5 to 10 mg, preferably from 2 to 5 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 6 2 41 - 6 or other mammals, the individual dose must be adapted in accordance with the body weight of the specific recipient.

For this purpose, it is also possible to use tablets with a breaking notch.

The pharmaceutical preparations of the present invention are obtained in a manner known per se, for example by methods selected from conventional mixing, granulating, coating and solution methods. Accordingly, a preparation can be obtained for example by combining the active ingredient with one or more solid carriers, optionally granulating the resulting mixture and processing the mixture or granules, if desired or necessary after the addition of suitable adjuncts, to the desired form of administration.

Suitable preparations for rectal administration are, for example, solutions for enema infusion and, in particular, suppositories and.gelatin rectal capsules.

A solution for enema application is preferably an aqueous solution which is prepared immediately before administration by dissolving a solid dosage unit form, preferably a tablet, in water of body temperature. Advantageously, such a solid preparation contains all essential constituents in a water-soluble form, for example an active ingredient of the invention as an acid addition salt, for example, the hydrochloride. Other suitable constituents are especially the conventional hydrotropic agents, disintegrators, buffers and compounds for altering the osmotic pressure. Suitable methods of production are the conventional tabletting methods.

Particularly preferred dosage forms for rectal administration are suppositories, which consist in principle particular of a combination of the active ingredient with a - 7 suppository base. Examples of suitable suppository bases are natural or synthetic triglycerides, paraffin hydrocarbons, polyethylene glycols or higher alkanols. It is, furthermore, 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 preparations for o'ral administration, for example tablets, sugar-coated tablets and capsules. Particularly advantageous preparations 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 ingredient is released slowly and continuously over a prolonged period of time, for example from 2 to 8 and preferably 4 to 6 hours. Such particularly preferred pharmaceutical forms of administration are for example tablets or sugarcoated 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 administration are in particular selected from fillers, for example, sugar, for example, lactose, saccharose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates, e.g. tricalcium phosphate or calcium hydrogen phosphate, - 8 also binders for example starch pastes, for example maize, corn, rice, or potato starch paste, gelatin, tragacanth, methyl cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose and polyvinylpyrrolidone, and/or, if desired, disintegrators, for example, the above starches, also carboxymethyl starch, crosslinked polyvinylpyrrolidone, agar, or alginic acid or a salt thereof, for example, sodium alginate. Adjuncts are chiefly glidants and lubricants, for example, silicic acid, talc, stearic acid or salts thereof, for example, magnesium stearate or calcium stearate, and/or polyethylene glycol. Sugar-coated tablet cores are provided with a suitable coating that can be resistant to gastric juices, using, inter alia, a concentrated sugar solution which may contain gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, a shellac solution in a suitable organic solvent or solvent mixture or, for the preparation of a coating resistant to gastric juices, a solution of a suitable cellulose preparation, for example, acetylcellulose phthalate or hydroxypropylmethylcellulose phthalate. The duration of effect of an intrinsically shortacting active ingredient 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 administration are dry-filled capsules, and also soft sealed capsules made from gelatin and a plasticiser, for example, glycerin or sorbitol. The dry-filled capsules can contain the active ingredient in the form of granules, for example of those - 9 described in more detail hereinafter. In soft capsules, the active ingredient is preferably dissolved or suspended in a suitable liquid, for example in a fatty oil, paraffin oil or liquid polyethylene glycol, to which a stabiliser can also be added.

A particularly advantageous form of the active ingredient/carrier mixture is a granulate which is suitable for processing to tablets, sugar-coated tablets or capsules. In addition to the active ingredient, such a granulate contains, one or more carriers selected inter alia, from diluents and fillers, for example, sugars, 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 hydrogen phosphate, as well as glidants, for example, talc or colloidal silicic acid, lubricants, for example, stearic acid or salts thereof, for example magnesium or calcium stearate, and/or polyethylene glycol, and also glycerides, for example, hydrogenated cotton 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 a moistening agent, for example, water or an organic solvent, for example ethanol, or a mixture 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 a suitable adjunct, excipient and/or coating substance. Such substances are in particular film formers for coatings, swelling substances with gel-forming properties for retarding diffusion, builders for embedding, in particular lipids, and plastics with thermoplastic properties. 341 - 10 To achieve the delayed and continuous release of the active ingredient, only one adjunct of the above kind is normally used.

Usually a water-insoluble adjunct is used in particular as a film former, for example a water-insoluble cellulose ether or ester for example, a cellulose lower alkyl alkyl ether, for example water-insoluble ethyl cellulose, or a water-insoluble cellulose ester containing hydroxyl groups which are esterified by one or more lower alkanecarboxylic acids and/or dicarboxylic acids, for example water-insoluble cellulose acetate· or cellulose acetate phthalate, a polymer or copolymer of an unsaturated aliphatic ester of a carboxylic acid with an alcohol, for example, a polymer or copolymer of an ester of a lower alkene-carboxylic acid with a lower alkanol, for example a copolymer 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 former, which comprises between 1% and 10%, preferably between 2% and 6%, of the total weight of the preparation formulation, is used chiefly for coating active ingredient particles or preferably a granulate, or also as an additive to a granulate, which can be. compressed to tablets. They can be applied or admixed in dissolved form using an organic solvent, for example an alcohol, such as ethanol, or an optionally chlorinated aliphatic hydrocarbon, for example methylene chloride, or a ketone, for example acetone, or a mixture thereof, or in the form of a dispersion, for example, a eoagulatable aqueous dispersion.

A suitable swelling substance is in particular an ether of cellulose which has a high degree of viscosity, for 62 41 - 11 example, a lower alkyl cellulose and in particular methyl cellulose with an average degree of substitution of about 1.8, and which is added preferably in powder form to the active ingredient or especially to a granulate thereof.

The resultant mixture is then processed, for example, to tablets. By this means there are obtained a pharmaceutical preparation which, on contact with water, swells 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 example cetyl alcohol or stearyl alcohol, and mixtures thereof. These lipids can be used for the release of the active ingredient 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 alkanecarboxylic 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, for example, hydrogenated vegetable oils, for example, hydrogenated cotton seed oil or hydrogenated castor oil, as well as mono-, di- or triesters of glycerol with palmitic acid or stearic acid or preferably a mixture 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 or polyvinyl or polyvinyl acetate type. fc> « a x - 12 The swelling substances and builders which are used in amounts of 5% to 70%, preferably of 10% to 40%, of the total weight of the preparation, are usually mixed with the active ingredient or preferably with an active ingredient/ adjunct mixture for example·, a granulated mixture, and, if appropriate after the addition of one or more further adjuncts, such as glidants and lubricants, compressed to tablets or capsule's.

It is a further object of the present invention to provide a method of treating mammals, excepting man, to alleviate and overcome diarrheal conditions by the enteral administration of one or more therapeutically effective doses of one or more analgesic peptides of the endorphine type, especially one of those specifically referred to herein, which comprises administering the active ingredient, advantageously in the form of an above described pharmaceutical preparation, in the indicated general or specific individual doses and in the manner as described above. Depending on the nature of the symptoms and the form of administration, as well as according to-individual requirements, the individual dose can be taken once or repeatedly. As a rule, the total dosage shall not exceed 10 individual doses in the course Of 24 hours.

The following Examples illustrate the invention.

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 compositions are prepared: Mixture A leuc ine-encephaline lactose, anhydrous, for direct tabletting cellulose, microcrystalline magnesium stearate 100 g 950 g 650 g g Mixture B leucine-encephaline lactose, microcrystalline, for direct tabletting hydrogenated castor oil, fine-grained 150 g 400 g 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 prepared from mixture A in an amount of 171 mg. Slightly domed punches having a diameter of S 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.

The enteric-coated tablets in batches of 100,000 are coated in a coating drum of 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 phthalate 0.662 kg diethyl phthalate 0.207 kg shellac 0.211 kg The temperature of the supply air is 60°C and the temperature of the cores is kept at about 25°C. The finished film46241 -14-coated tablets are subsequently dried for 12 hours at 30°C. Example 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 iri the rapid-acting form and 6 mg in the slowre lease form. The mixtures required for preparing the tablets have the following composition: Mixture A methionine-encephaline 40 g lactose, anhydrous, for direct tabletting 1000 g 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 1.

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 particle size of about 125 μ. 400 g lactose, finely ground calcium stearate 200 g 50 g Size 2 hard gelatin capsules, which during the capsule manufacturing process have been made resistant to solution in gastric fluid by being dipped in an organic solution of hydroxy-propylmethylcellulose (type HP 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-encaphaline 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 required for these capsules have 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 in Example 3.

Claims (20)

1. A pharmaceutical preparation for enteral administration which comprises as active ingredient, one or more analgesic peptides of the endorphine type, as hereinbefore defined.

2. A pharmaceutical preparation as claimed in claim 1, which comprises as active ingredient one or more peptides having a β-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 analogous thereof, wherein one of the amino acids of the original sequence is exchanged for another amino acid, or a derivative thereof.

3. A pharmaceutical preparation as claimed in claim 1 or claim 2, which comprises as active ingredient a pentapeptide characterised by the β-lipotropin amino acid partial sequence 61-65, wherein one of the original amino acids may be exchanged for another amiho acid, or an acid addition salt or Cterminal amide thereof.

4. A pharmaceutical preparation as claimed in any one of claims 1 to 3, which comprises as active ingredient leucineencephaline of the formula H-Tyr-Gly-Gly-Phe-Leu-OH or an acid addition salt or C-terminal amide thereof.

5. A pharmaceutical preparation as claimed in any one of claims 1 to 4, which comprises 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.

6. A pharmaceutical preparation as claimed in any >46241 - 17 of claims 1 to 5, which comprises the active ingredient in conjunction or admixture with one or more inert, physiologically tolerable carriers and/or adjuncts.

7. A pharmaceutical preparation as claimed in any one of claims 1 to 6, in the form of dosage units.

8. A pharmaceutical preparation as claimed in any one of claims 1 to 7, for oral administration.

9. A pharmaceutical preparation as claimed in any one of claims 1 to 7, for rectal administration.

10. A pharmaceutical preparation as claimed in any one of claims 1 to 8, in the form of tablets, coated tablets or capsules, which are resistant to solution in gastric fluid and disintegrate in the intestine.

11. A pharmaceutical preparation as claimed in claim 10, which comprises 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 intestine.

12. A pharmaceutical preparation as claimed in any one of claims 1 to 11, wherein the content of an active ingredient, or the total content of several such active ingredients, is from 0.5 to 100 mg per dosage unit for administration to adults.

13. A pharmaceutical preparation as claimed in any one of claims 1 to 12, wherein the content of leucine-encephaline is from 5 to 100 mg per dosage unit for administration to adults.

14. A pharmaceutical preparation as claimed in claim 13, wherein the content of leucine-encephaline is from 20 to 50 mg per dosage unit for administration to adults. - 18

15. A pharmaceutical preparation as claimed in any one of claims 1 to 12, wherein the content of methionine-encephaline is from 0.5 to 10 mg per dosage unit for administration to adults. 5

16, A pharmaceutical preparation as claimed in claim 15, wherein the content of methionine-encephaline is from 2 to 5 mg per dosage unit for administration to adults.

17. A pharmaceutical preparation as claimed in claim 1, substantially as described in any one of the Examples herein. 10

18. A process for the production of the pharmaceutical preparations as claimed in claim 1, which comprises combining the active ingredient or ingredients with at least one carrier and/or adjunct, granulating a resulting mixture, if desired or necessary, and processing the mixture of granulate,

15. Optionally using one or more further adjuncts, to the desired administration form.

16.

19. A method of treating mammals excepting man to alleviate or overcome diarrheal conditions by the enteral administration of one or more therapeutically effective doses of ohe or more

17. 20 analgesic peptides of the endorphine type as hereinbefore defined.

20. A method as claimed in claim 19, wherein the administration is made in the form of a pharmaceutical preparation claimed in any one of claims 1 to 17.