MXPA98006855A

MXPA98006855A - Salts of morphine and diamorphine of anionic analyzes, non-narcotics, of the type of carboxylic acids substituted, processes for their production, its application and the pharmaceutical preparations containing these sa

Info

Publication number: MXPA98006855A
Application number: MXPA/A/1998/006855A
Authority: MX
Inventors: Muller Walter; Asmussen Bodo; Riess Walter
Original assignee: Lts Lohmann Therapiesysteme Gmbh 56567 Neuwied De
Priority date: 1996-02-28
Filing date: 1998-08-24
Publication date: 1999-09-20

Abstract

The present invention relates to: The object of the present invention are morphine and diamorphine salts of non-narcotic anionic analgesics of the type of substituted carboxylic acids, preferably the salts of morphine and diamorphine of diclofenac (formula 1), process for obtaining them, the use of these salts for the treatment of diseases, as well as pharmaceutical preparations containing these salts

Description

SALTS OF MORPHINE AND DIAMORRHINE ANALGESICOS ANIONICQS. NOT NARCOTICS. OF THE TYPE OF SUBSTITUTE CARBOXYLIC ACIDS: PROCESSES FOR ITS PRODUCTION, ITS APPLICATION AND THE PHARMACEUTICAL PREPARATIONS CONTAINING THESE SALTS.

Field of Invention The object of the present invention are morphine salts of anionic, non-narcotic analgesics, of the type of substituted carboxylic acids, preferably the morphine and diamorphine salts of diclofenac (formula 1), method for their preparation, the application of these salts for the treatment of diseases, as well as pharmaceutical preparations containing these salts.

Background of the Invention One of the most frequent symptoms of an illness or an injury is pain. Even when the pain has to be understood as a warning sign and protection of the organism, the patient in question usually asks to be REF .: 28113 administer analgesic substances or at least painkillers. Therefore, one of the central desires of medicine is to dispose of these substances. These substances, the so-called analgesics, used in therapeutic doses, will reduce or suppress the sensation of pain, without this dosage having a general anesthetic effect. Considering its degree of efficacy, the mechanism of action and the side effects, two groups of analgesics are distinguished: analgesics with central and powerful action, and analgesics with rather peripheral action from weak to semi-potent. When centrally acting active substances are used, habituation symptoms that can reach dependence may occur. An example of these centrally acting active substances that entail this risk is morphine (formula 3a). morphine is on the market in the form of its inorganic salts, for example its sulfate hydrochloride, to combat severe post-traumatic or postoperative pain as well as chronic pain, for example in the case of advanced cancer, and is used parenterally and oral. A derivative of morphine, diacetylmorphine (formula 3b), which is also known as diamorphine or heroin, is sold and consumed without any pharmacological, pharmaceutical and pharmacokinetic control. Its qualified use in the therapy of drug addiction continues to be a scientific and sociological problem not yet solved.

In order to reduce the risk of addiction to morphine in the clinical use of morphine-based preparations, other analgesics, preferably non-narcotic preparations, having peripheral action, are administered simultaneously or alternatively. The large number of peripherally acting analgesics, their differences in terms of potency and therefore in terms of dosage, generate great uncertainty when choosing the preparations to be combined and cause discomfort in patients due to the amount of drugs they have to take .

Grant of the Invention What is intended with the present invention is to offer new analgesics that have minimal side effects and a maximum analgesic action.

This problem is solved with the new active substances mentioned in the claims and the pharmaceutical preparations containing these active substances.

The active substances according to the invention are the morphine and diamorphine salts of anionic, non-narcotic analgesics of the type of substituted carboxylic acids. The anionic, non-narcotic analgesics of the type of substituted carboxylic acids that can be used are the following: Diclofenac, Indomethacin, Sulindac, Ketoprofen or Fenbufen.

Preferably the invention encompasses the salts of morphine diclofenate (formula la) and diamorphine diclofenate (formula Ib), which consist of the peripherally acting anionic analgesic Diclofenac ([2 - [(2,6-dichlorophenyl) -amino] - phenyl] acetic (formula 2) and the cationic analgesic, centrally acting, morphine (formula 3a) or its derivative, diacetylmorphine (formula 3b), also called diamorphine In formula 1, R can be H or CH 3 CO. H, it is morphine-diclofenate (formula la), if R is equal to CH3CO, it is diamorphine-diclofenate (formula Ib).

)) The aforementioned non-narcotic analgesics of the type of substituted carboxylic acids are known. The sodium, potassium and diethylammonium salts of diclofenac (formula 2) acid ([2 - [(2,6-dichlorophenyl) -amino] phenyl] acetic acid is used, for example, for the treatment of painful inflammatory processes, which are commercially available for oral, rectal, parenteral or topical use.

Diclofenac (formula 2) turns out to be the most potent non-steroidal analgesic / anti-inflammatory due to the effective dose and total clearance (Clearance).

Formula In the case of buccal use, Diclofenac (formula 2) is effective from the clinical-pharmacological point of view in doses between 0.08 to 0.16 mmol / 8 hours, so it is within the scope of the molar dosage of morphine (formula 3a). By way of comparison, morphine is effective in doses between 0.035 to 0.35 mmol / 6 hours.

Formula 3 (formula 3a: R = H) (formula 3b: R = CH3CO) In formula 3, R can be equal to H morphine) or CH3CO (diamorphine).

The salts according to the invention, composed of the base of the narcotic analgesic of the formula 3, in which R is equal to H or CH 3 CO, and of the non-narcotic analgesic acid of the type of substituted carboxylic acids, preferably the diclofenac of morphine or diamorphine (formula Ia or Ib) advantageously allow the partial components to be used in lower dosages than the preparations of the monosubstances in the form of their organic salts, in free combination which are usually found in the usual commercial administration forms. The salts according to the invention, preferably morphine diclofenate or diamorphine (formula la or Ib) can be used in place of the traditional morphine preparations, although with fewer side effects, to alleviate pain. In the case of the diclofenates according to the invention, the limits of gastrointestinal tolerance of Diclofenac (formula 2) constitute a guarantee that official recommendations for dosing will be taken into account. The morphine or diamorphine salts according to the invention therefore make possible the possible drug abuse which entails the possibility of disposing morphine-based preparations. The morphine or diamorphine salts, according to the invention, allow the doctor to better plot a treatment program for the patient since there are fewer drugs in free combinations and many variations can not be made with respect to the medical recommendation.

The diamorphine salts according to the invention make it possible to include diamorphine in therapy for the first time.

The topical preparations of the salts according to the invention, in particular, morphine diclofenate (formula la) and diamorphine diclofenate (formula Ib) allow, for example, in the detoxification phase of addiction therapy, the minimum necessary amount of active substance, with reduced systemic side effects.

The active substances according to the invention are obtained from the basic components and / or acids already known. It is preferred to react non-narcotic analgesics of the unsubstituted carboxylic acid type, in particular ([2- [(2,6-dichlorophenyl) -amino] -phenyl] -acetic acid, of the formula 2 or a basic salt thereof with, preferably, the equimolar amount of at least morphine (formula 3a) or the morphine derivative of formula 3b or a suitable salt thereof The salts of the non-narcotic analgesics of the substituted carboxylic acid type which are used they are in particular base salts which can be easily separated from the reaction mixture For example, the bases which are more volatile or weaker than morphine or diamorphine (formula 3a or 3b), or with the anionic analgesic, can be mentioned. non-narcotic of the type of substituted carboxylic acids, in particular with ([2- [(2,6-dichlorophenyl) -amino] -phenyl-acetic acid of formula 2, more easily form soluble salts than the salts according to the invention. that is, for example, other organic ammonium salts. Metallic salts can also be used, which in reaction with an appropriate acid salt of morphine or diamorphine (formula 3a or 3b) form sparingly soluble salts of these acids, for example calcium salts.

The morphine or diamorphine salts (formula 3a or 3b) which are used according to the process are, for example, salts with acids which can be separated from the reaction mixture, for example salts of volatile acids. It is also possible to use weaker acids than the non-narcotic analgesic of the type of the substituted carboxylic acids, or which form hardly soluble salts with metal cations, for example CA2 +. They are salts of morphine or diamorphine (formula 3 a or 3b), for example salts of the compounds according to formula 3a or 3b, with inorganic acids, for example hydrochlorides, sulfates or phosphates or salts of morphine or diamorphine (formula 3a or 3b) and organic acids such as fumarates, maleates or oxalates.

The reaction of non-narcotic analgesics of the type of substituted carboxylic acids, preferably ([2 - [(2,6-dichlorophenyl) -amino] -phenyl acetic acid (formula 2) with a base of formula 3 is carried out by Preference in an inert solvent If necessary, the reaction can be carried out by cooling or heating, for example at temperatures between 0 and 100 ° C, preferably at room temperature The reaction can be carried out in a closed vessel and / or under an atmosphere of inert gas, for example under a nitrogen atmosphere.

Inert solvents that can be used are for example: alcohols, ethers, ketones, carboxylic esters, amides, sulfoxides, chlorinated hydrocarbons or mixtures of these solvents. The alcohols that can be used are: low molecular weight alcohols, preferably methanol or ethanol, such as diallyl ether of low molecular weight, preferably diethylether, cyclic ether, preferably "dioxane or tetrahydrofuran, ketones can be: dialkyl ketones of low molecular weight, preferably acetone, the carboxylic esters can be: low molecular weight alkylcarboxylaryl esters, preferably acetylester ethyl, the amides can be low molecular weight N, N-dialkylamides, preferably N, N-dimethylformamide , the sulfoxides may be: low molecular weight dialkylsulphoxides, preferably dimethyl sulfoxide and the chlorinated hydrocarbons may be methylene chloride or chloroform.

Non-narcotic analgesics of the type of substituted carboxylic acids, in particular ([2 - [(2,6-dichlorophenyl) -amino] -phenyl] -acetic acid (formula 2), can also be formed under the reaction conditions, starting from the corresponding esters, for example low molecular weight alkyl ester, by hydrolysis in the presence of a base, for example NaOH The morphine or diamorphine of the formula 3a or 3b can also be released, under the reaction conditions, from the acid salts , preferably the hydrochlorides, sulfates or phosphates in the presence of stoichiometric amounts of suitable bases, for example NaOH.

In a preferred embodiment of the method, the non-narcotic analgesic of the substituted carboxylic acid type is reacted as free acid according to formula 2 in a suitable solvent, directly with the morphine or the diamorphine of formula 3a or 3b as the base. The invention also relates to those manufacturing methods in which the starting substances are produced in-house or a starting material is obtained, under the reaction conditions, from a derivative and / or is used in the form of a mixture of substances, for example in the case of morphine or diamorphine (formula 3a or 3b) as a mixture of crude alkaloid. The invention also relates to processes in which liquid or solid absorbers, whether charged or uncharged, inorganic or organic, are used. Thus, for example, ion exchangers can be used to bind the cationic or anionic components of the salts according to the invention, which subsequently react with the complementary anionic and / or cationic components. Inorganic and non-charged organic absorbers can be used to prepare or clean the salts according to the invention.

The invention also relates to pharmaceutical preparations which, in addition to the known pharmaceutical auxiliary materials, contain the salts based on morphine (formula 3a) or diacetylmorphine (formula 3b) and analgesic carboxylic acids, in particular the salts of the formulas la and Ib. , morphine diclofenate and diamorphine as well as the procedure for obtaining these pharmaceutical preparations. The preparations according to the invention are those for enteral administration, for example oral or rectal, of parenteral application, for example intravenous, intramuscular or subcutaneous, or topical, containing the salts according to the invention, in particular the salts of formula la and Ib alone or together with carrier materials of pharmaceutical application, suitable in particular for the controlled release of active substance.

In unit dosage forms for buccal use, the content of active substance according to the invention preferably ranges between 10 and 90%. For the manufacture of tablets or dragee cores, the active substance is combined, for example, with powdered solid carriers such as lactose, sucrose, sorbitol, mannitol, starches or amylopectin, and also cellulose derivatives, gelatin or polyvinylpyrrolidone, optionally adding lubricants such as magnesium or calcium stearate or polyethylene glycols as well as highly dispersed silicic acid. The dragee cores are coated, for example, with concentrated sugar solutions, which may also contain other additives such as, for example, gum arabic, talc and / or titanium dioxide or with a lacquer dissolved in highly volatile organic solvents or mixtures of solvents. Dyes can be added to these coatings, for example to mark the various doses of active substance. Oral administration forms are also suitable for gelatin-based capsules as well as closed soft gelatin capsules and a softening agent such as glycerin. The former contain the active substance according to the invention, preferably in the form of granules mixed with lubricant, such as talc or magnesium stearate and optionally stabilizers, sodium pyrosulfite (Na2S205) or ascorbic acid. In soft capsules, the active substance according to the invention is preferably dissolved or suspended in suitable liquids such as liquid polyethylene glycols, stabilizers can also be added. In addition, the active substances according to the invention can be introduced, for controlled release, into an acceptable pharmaceutical carrier matrix or into a membrane-limited reservoir which is activated in vivo and the corresponding release kinetics are produced.

With unit dosage forms for rectal application, for example, suppositories formed by the active substance salt according to the invention are used in a suppository mass of the natural or synthetic triglyceride base of suitable melting point, for example cocoa butter or polyethylene glycols or suitable higher fatty alcohols.

For parenteral administration, solutions of the active substance according to the invention and suspensions are preferably used, such as oil suspensions for injection where suitable lipophilic solvents or vehicles are used, such as oils, for example sesame oil or synthetic fatty acid esters, example ethyl oleate and triglycerides, or aqueous suspensions for injection containing substances which increase the viscosity, for example sodium carboxymethyl cellulose, sorbitol and / or dextran and optionally also stabilizers.

Topical pharmaceutical preparations of the salts according to the invention, preferably of morphine cyclopenate (formula la) or diamorphine diclofenate (formula Ib) are creams, ointments, gels, pastes, foams, dyes and solutions containing more or less than 0.5 to 20% of the active substance according to the invention. A salt according to the invention, preferably morphine diclofenate (formula la) or diamorphine diclofenate (formula Ib) can also be incorporated in patches or in the so-called percutaneous therapeutic systems (TTS), from which the components of the active substance on The skin, on a defined surface of the skin, occlusively with controlled emission rate or conveniently applied for percutaneous resorption.

The following examples are intended to clarify the invention, without this implying any limitation: Method of manufacture of salts Example 1; To an aqueous solution of morphine hydrochloride, an equimolar amount of an aqueous solution of diclofenac sodium salt is added and dissolved by stirring and optionally heating. The precipitate of morphine diclofenate obtained is drained and dried in the desiccator on a sieve by molecular action.

In infrared spectroscopy, parts of morphine and Diclofenac can be detected in the crystalline substance.

The melting point of the salt is 143 ° C and therefore clearly differs from the melting point of the starting substances (morphine hydrochloride: 255 ° C, diclofenac sodium salt: '280 ° C).

Example 2; Equimolar amounts of the morphine base and / or diamorphine and ([2 - [(2,6-dichlorophenyl) -amino] -phenyl] acetic acid are dissolved in ethanol, mixed in the round-bottomed balloon and concentrated to drying in the rotary evaporator The residue of the concentration is recrystallized from ethanol by adding petroleum ester, drained and dried in vacuo.

Example 3; 1 millimole of diamorphine acid sulfate and / or morphine acid sulfate is dissolved, made alkaline with aqueous sodium bicarbonate solution and extracted with acetic ester. 1 millimole Diclofenac sodium is also dissolved in water, acidified with dilute hydrochloric acid and extracted with acetic ester. The two extracts are dried separately over anhydrous sodium sulfate.

The two extracts are then combined, mixed and concentrated in a round-bottomed flask on the rotary evaporator until it is dried. The residue of the concentration is recrystallized from ethanol, using petroleum ether and dried in vacuum.

Method of manufacturing a pharmaceutical preparation Example 4; For buccal administration, the morphine and / or diamorphine diclofenate is finely milled and mixed homogeneously with powdered carrier substances such as lactose, sucrose, sorbitol, mannitol or starches to obtain a four times higher amount. Individual doses of, for example, 0.05 millimole of active substance equivalent are dosed in gelatin capsules.

It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Having described the invention as above, the content of the following is claimed as property.

Claims

1. A salt of a cationic narcotic analgesic with a non-narcotic analgesic anionic, characterized because the base of narcotic analgesic corresponds to the formula Formula 3 where R is equal to H or to CH3C0 and the non-narcotic analgesic belongs to the type of the substituted carboxylic acids.

2. The salt according to claim 1, characterized in that the anion of the non-narcotic analgesic of the type of the substituted carboxylic acids is Diclofenac, Indomethacin, Sulindac, Ketoprofen or Fenbufen, preferably Diclofenac.

3. A process for obtaining the salt according to claim 1 or 2, characterized in that the base of the narcotic analgesic corresponds to the formula 3 in which & is equal to H or CH3C0 or a suitable salt thereof, reacts with the non-narcotic analgesic acid of the substituted carboxylic acid type or a basic salt thereof in an inert solvent, in an area of temperatures comprised between 0 and 100 ° C.

4. The method according to claim 3, characterized in that a salt of the non-narcotic analgesic of the type of the carboxylic acids substituted with bases more volatile or weaker than the base of the narcotic analgesic of the formula 3 is used, in which R is equal to H or CH3CO or a non-narcotic analgesic salt of the substituted carboxylic acid type, with bases forming with the non-narcotic analgesic of the substituted carboxylic acid type, salts more readily soluble than the salt of claim 1.

5. The process according to claim 4, characterized in that an organic ammonium salt or a metal salt, preferably a calcium salt, is used as the salt.

6. The method according to one of claims 3 to 5, characterized in that a salt of the base of the narcotic analgesic of formula 3 is used, in which R is equal to H or CH 3 CO, with acids more volatile or weaker than the analgesic acid non-narcotic of the type of the substituted carboxylic acids or a salt of the base of the narcotic analgesic of formula 3, wherein R is equal to H or CH 3 CO, with acids that form metal cations, preferably with Ca 2+, hardly soluble salts.

7. The method according to claim 6, characterized in that a salt of the base of the narcotic analgesic of formula 3 is used, in which R is equal to H or CH 3 CO, with inorganic acids, preferably a hydrochloride, sulfate or phosphate or a salt of the base of the narcotic analgesic of formula 3, in which R is equal to H or CH3CO, with organic acids, preferably a fumarate, maleate or an oxalate.

8. The process according to one of claims 3 to 7, characterized in that Diclofenac ([2 - [(2,6-dichlorophenyl) -amino] -phenyl] acetic acid is used as the non-narcotic analgesic acid of the substituted carboxylic acid type.

9. The process for obtaining the salt according to claim 1 or 2, characterized in that an acid salt of the basic narcotic analgesic of formula 3 is reacted, wherein R equals H or CH 3 CO, preferably the hydrochloride, sulfate or phosphate , with an ester of the non-narcotic analgesic of the substituted carboxylic acid type, preferably a low molecular weight alkyl ester, in the presence of a base, preferably NaOH, in an inert solvent within a temperature range of 0 to 100. ° C.

10. The process for obtaining the salt according to claim 1 or 2, characterized in that the base of the narcotic analgesic of formula 3, in the R is equal to H or CH 3 CO, is reacted with the non-narcotic analgesic acid of the type of substituted carboxylic acids, in an inert solvent, within temperatures between 0 and 100 ° C.

11. The method according to one of claims 9 to 10, characterized in that the base of the narcotic analgesic according to formula 3, in which R is equal to H or to CH 3 CO, is used in the mixture as a crude alkaloid extract.

12. The process for obtaining the salt according to claim 1 or 2, characterized in that the cation or base of the narcotic analgesic of formula 3, in which R is equal to H or CH 3 CO, or the anion or the non-narcotic analgesic acid of the type of the substituted carboxylic acids are linked to liquid or inorganic or organic solids, charged or uncharged, preferably ion exchangers and are reacted with the anionic and / or cationic complementary component in an inert solvent, within an area of temperatures between 0 and 100 ° C.

13. The process according to one of claims 3 to 12, characterized in that at least equimolar amounts of the reaction products are used.

14. The process according to one of claims 3 to 13, characterized in that the reaction is carried out at room temperature and / or under an inert gas atmosphere, and preferably under a nitrogen atmosphere.

15. The process according to one of claims 3 to 14, characterized in that alcohols, ethers, ketones, carboxylic ester, amides, sulfoxides, chlorinated hydrocarbons or mixtures of these solvents are used as the inert solvent.

16. The process according to one of claims 3 to 15, characterized in that alcohols of low molecular weight, preferably methanol or ethanol, such as ethers, low molecular weight dialkyl ethers or cyclic ethers, preferably diethyl ether, dioxane or tetrahydrofuran, are used as alcohols. as ketones, dialkyl ketones of low molecular weight, preferably acetone, such as carboxylic esters, low molecular weight carboxylic alkyl esters, preferably ethyl ester, such as amides, low molecular weight N, N-dialkylamides, preferably N, N-dimethylformamide, as sulphoxides, dialkylsulphoxides, low molecular weight dialkylsulphoxides, preferably dimethyl sulfoxide and as chlorinated hydrocarbons, preferably methylene chloride or chloroform or mixtures of these solvents.

17. A pharmaceutical preparation characterized in that in addition to the known auxiliary pharmaceutical materials it contains a salt according to claim 1 or 2.

18. The pharmaceutical preparation according to claim 17, characterized in that it is for enteral application, for example buccal or rectal or parenteral, for example intravenous, intramuscular, subcutaneous or topical.

19. The use of the salt according to claim 1 or 2 in the form of galenic preparations or for the preparation thereof.

20. The salt according to claim 1 or 2, for the therapeutic treatment of the human or animal organism.

21. The salt according to claim 1 or 2, for the therapeutic treatment of pains.

22. The pharmaceutical preparation according to claim 17 or 18, for the therapeutic treatment of the human or animal organism.

2. 3 . The preparation or preparation according to claim 17 or 18, for the therapeutic treatment of pains.

24. A process for the production of a preparation for therapeutic treatment of human or animal organisms, characterized in that the salt is used according to any of claims 1 or 2 or a pharmaceutical preparation according to any of claims 17 or 18.

25. A process for the production of a preparation for the treatment of pain, characterized in that the salt is used according to any of the claims 1 or 2 or a pharmaceutical preparations according to any of claims 17 or 18.