WO2001003774A2

WO2001003774A2 - Pharmaceutical composition for the treatment of calcification

Info

Publication number: WO2001003774A2
Application number: PCT/HU2000/000053
Authority: WO
Inventors: Zoltán Dárdai
Original assignee: Individual
Current assignee: Individual
Priority date: 1999-07-07
Filing date: 2000-06-02
Publication date: 2001-01-18
Anticipated expiration: 2002-01-07
Also published as: WO2001003774A3; HU9902296D0; AU5416500A

Abstract

The invention relates to a pharmaceutical (including veterinary) composition for the treatment of calcification. The composition according to the invention is (a) either a topically applicable composition, or (b) an injectable composition or an infusion, and comprises as active agent acetylsalicylic acid either as a free acid or as its pharmaceutically acceptable water-soluble salt or as its pharmaceutically acceptable water-soluble biologically labile ester, together with a carrier, a diluent and/or an other auxiliary agent conventionally used in such compositions.

Description

PHARMACEUTICAL COMPOSITION FOR THE TREATMENT OF CALCIFICATION

The invention relates to pharmaceutical compositions (including veterinary compositions, too) which can be used in the therapy of calcification.

Calcification of cartilages, joints and interior organs (such as liver, spleen, bile) is a disorder impending over everyone with the progress in lifetime; said disorder plays a causative role in the development of numerous diseases or medical conditions (such as joint inflammations, rheuma, locomotor diseases, deformations, etc.). Numerous therapeutical methods have been known for the treatment of calcification and its consequences. These methods include non-drug treatments (such as diet, curative gymnastics, massage, mud pack, balneotherapy, etc.) and various drug therapies (such as administration of antiphlogistic, analgesic, muscle-relaxant etc. agents), which are frequently used in combination. As a common feature, none of the therapies used at present can cease the once-established calcification; only the progress of the disease can be slowed down and the secondary symptoms can be alleviated. Pharmaceutical compositions used for internal therapy have the disadvantage that the administered active agent cannot reach the site of calcification in a targeted manner but it exerts a loading on the entire organism, which frequently leads to undesired side-effects. The ulcerative effects of certain orally administered non-steroidal anti-inflammatory drugs, applied to alleviate rheumatic inflammations, can be mentioned as an example.

The invention aims at providing pharmaceutical compositions (including veterinary compositions, too) which can be used either to cease already established calcification or to considerably reduce its extent, and which, when administered in a preferred form, can be directed in a targeted manner (i.e. without exerting an un- necessary loading on the whole organism or on the organs requiring no treatment) to the organ or region where calcification should be ceased or its extent should be reduced.

Based on my tests performed on isolated animal organs I have found, surprisingly, that acetylsalicylic acid and its pharmaceutically acceptable water-soluble salts and its pharmaceutically acceptable water-soluble biologically labile esters are suitable to cease already-established calcifications. This recognition forms the basis of the present invention.

Thus, the invention relates to a pharmaceutical (including veterinary) composition for the treatment of calcification. The composition according to the invention is

(a) either a topically applicable composition, or

(b) an injectable composition or an infusion, and comprises as active agent acetylsalicylic acid either as a free acid or as its pharmaceutically acceptable water-soluble salt or as its pharmaceutically acceptable water-soluble biologically labile ester, together with a carrier, a diluent and/or an other auxiliary agent conventionally used in such compositions.

The terms "salt" and "biologically labile ester" refer to salts and esters, respectively, which undergo hydrolysis or double decomposition under physiological conditions in the presence of a carbonate. Such derivatives of acetylsalicylic acid are e.g. its alkali metal and ammonium salts (including quaternary ammonium salts, too), and its esters formed with lower alkanols and aminoalkanols compπsing pre-ferably 1-3 carbon atoms. Acetylsalicylic acid and its derivatives discussed above react with the calcive deposit, and remove the calcive deposit in the form of calcium acetylsalicylate, which latter is a well-known, tested pharmaceutical substance. Acetylsalicylic acid has been known since more than 100 years, and it has been widely used in the therapy, either as such or in the form of its salts, as an antiphlogistic, antipyretic and pain-relieving agent. However, no data can be found in the literature on a possible anti-calcificative effect of acetylsalicylic acid, and neither acetylsalicylic acid itself nor its salts and esters discussed above have been utilized in a form suitable for targeted therapy (i.e. as a topically applicable composition or as an injection or infusion to be administered into the organ requiring therapy).

Thus, one group of the pharmaceutical compositions according to the invention consists of topically applicable compositions, which may be e.g. solutions, emulsions, suspensions, ointments, creams, gels, lotions, shake-up mixtures, plasters and similar formulations routinely used in topical treatments. These compositions comprise, beside the active agent, carriers, diluents and/or other auxiliary agents conventionally applied in such compositions, examples of which are as follows: ointment bases, such as vaseline and lanonile; solvents and liquid diluents, such as water; alcohols and glycerol; thickeners and gellifying agents, such as poly- vinyl alcohol, polyvinyl acetate and polymeric cellulose derivatives; ionic and non- ionic tenzides; odourants; substances for adjusting osmotic pressure; colourants and dyestuffs. Preferred representatives of topical compositions are those comprising a thickener, optionally along with a stabilizer, since they enable one to apply a relatively high local dose onto the area to be treated. The topical compositions may optionally also comprise other biologically active substances as activity-complementing agents, examples of which are as follows: antiphlogistic agents, analgesic agents, antirheumatic agents, muscle relaxants, local anaesthetics, pore dilatators and/or agents alleviating skin irritations. The activity-complementing agents also comprise active agents utilized in conventional formulations for the topical treatment of joint and rheumatic pains, such as camphor, menthol, lidocain, methyl salicylate, snake venom extract, and the like. Preferably the topical compositions also comprise agents for dilatating skin pores and/or vasopermeability-increasing agents as activity-complementing substances; such compositions can also reduce vascular sclerosis by transdermal way.

The active agent content of topically applicable compositions may vary with the type of the formulation concerned. The active agent content of such compositions may be generally 0.1-20 % by weight, preferably 0.5-15 % by weight, more preferably 1-10 % by weight. The amounts of pore dilatators and/or vasopermeability-increasing agents (such as capsaicine and/or histamine), if present, may be generally 0.01-2 % by weight, preferably 0.05-0.5 % by weight. The amounts of other activity-complementing agents, which can be optionally admixed into the topical compositions, may vary within wide limits; the actual values depend mainly on the type and effect of the agents concerned and on their compatibility with the other components of the composition.

Injectable compositions and infusions may contain, beside the active agent, a wide variety of auxiliary agents well known from pharmacotechnology, examples of which are liquid diluents, buffers and salts for adjusting osmotic pressure. If desired, injectable compositions and infusions may also contain activity-complementing agents, such as antithrombotic, antiphlogistic, analgesic or antipyretic agents. A combined use with an analgesic agent assists in the early mobilisation of the patient. Upon moving, the active agent reaches more quickly the targeted organ, where (due to commonly known crystalphysical reasons) the dissolution process starts at the calcic peaks, which are the main causatives of rheumatic pains. Injectable compositions and infusions may also contain the active agent in sustained-release form. This can be done by conventional methods; thus e.g. the active agent may be entrapped into a cyclic starch or may be microencapsulated into a biodegradable material. If desired, even topical formulations may contain the active agent in sustained-release form. This has the additional advantage that when appropriately selected enveloping materials are used, the initially hydrophylic active agent can be converted into a form which can easily be combined with hydrophobic carriers.

Injectable compositions and infusions may contain generally 0.01-2 % by weight, preferably 0.005-0.5 % by weight of active agent, taken in non-enveloped form.

All of the above percentages relate to the total weight of the composition.

The pharmaceutical compositions according to the invention may be prepared by conventional pharmacotechological operations well known to one skilled in the art.

In order to treat calcification, the composition according to the invention is applied onto the body part or into the organ to be treated. When cartilage-, joint- and parosteal calcifications are to be treated, it is preferred to use a topical formulation which is applied onto the region to be treated. However, for this purpose an injectable formulation can also be introduced into the body part at the location of calcification. When calcifications of interior organs (such as of liver or kidney) are to be treated, it is most preferred to use an injectable formulation to be introduced just into the organ concerned. For the parenteral treatment of vascular sclerosis it is preferred to use intravascular formulations or infusions which, when introduced into the blood vessels concerned, cause only a minimum gas evolution if at all. These compositions may comprise CO₂-absorbing components or may comprise acetylsalicylic acid as its ammonium salt, quaternary ammonium salt or ester formed with an amino alcohol.

Further details of the invention are illustrated by the following non-limiting Examples.

Example 1

3 g of Diclofenac (an antiphlogistic agent), 2 g of camphor (an agent alleviating skin irritations) and 0.2 g of capsaicine (a pore dilatating agent) were dissolved in 35 g of 96 v/v % ethanol. 2.5 g of acetylsalicylic acid, 2 g of glycerol, 5 g of methyl cellulose and 0.3 g of a nonionic tenside were admixed with 50 g of water, and the alcoholic solution prepared as described above was admixed with the resulting hydrogel. A gel for topical administration was obtained.

Example 2

A concentrated aqueous solution of 3 g of acetylsalicylic acid and of 2 g of lidocain (a loc,al anaesthetic) and a concentrated alcoholic solution of 0.2 g of histamine were admixed with 90 g of a hydrophilic pharmaceutical ointment base (Ph.Hg.V). An ointment for topical administration was obtained.

Example 3

0.1 % by weight of lidocain, 0.5 % by weight of acetylsalicylic acid and 0.01 % by weight of a nonionic surfactant were dissolved in Ringer solution. An infusion was obtained.

Example 4

4 g of acetylsalicylic acid were entrapped into cyclodextrin by a known technology, and the resulting product was added to 1000 ml of sterile water containing 0.1 % by weight of lidocain and 0.1 % of a nonionic surfactant. An emulsion for intramuscular administration, comprising the active agent in a sustained-release form, was obtained.

Activity tests and their results: A. Tests performed on isolated pig joints

2.11 g of calcium carbonate were crystallized onto a pig joint with intact membrane. The thus-treated joint part, about 6.5 cm in diameter, was wrapped in parchment, 10 ml of physiological saline were poured into the gap between the parchment wrap and the joint, and the edges of the parchment were fixed to the joint with a water-impermeable adhesive tape. The surface of the parchment wrap covering the calcium carbonate-treated part of the joint was smeared daily twice with about 4 g, each, of a cream comprising 3 % by weight of acetylsalicylic acid and 0.1 % by weight of capsaicine in a hydrophilic pharmaceutical ointment base. Aliquots were removed from the physiological saline solution at regular intervals, their calcium contents were measured, and the amounts of calcium carbonate dissolved by the time of measurement were calculated. The amounts of dissolved calcium carbonate as a function of time were as follows:

Time, hours Dissolved CaCO^, g

24 0.4

48 0.9

72 1.4

96 1.9

168 2.05

The test described above was repeated with the difference that the pig joint was cut with a chopper to injure the surface of the joint membrane, and thereafter 2.18 g of calcium carbonate were crystallized onto the thus-injured joint. Within the limits of error, the progress of CaCO_s dissolution was the same as observed before. As an outstanding result, the composition according to the invention did not damage the original cartilage/bone parts.

B. Tests performed on dogs

The tests were performed on four heavily built Hungarian sheep-dogs, all being older than 11 years, which had difficulties in moving their hind legs. The hair was shaved off from the hind legs of the dogs, and the regions where calcification was found by X-ray examination were smeared once a day with an ointment containing 2 % by weight of Diclofenac-Na, being otherwise of the same composition as described in Example 2. After 2 days of treatment all the four animals could move much better, and no veterinarily observable movement disorder could be detected on them after 7 days of treatment. After 4 weeks of treatment no calcification could be detected on the animals by X-ray examination.

Claims

_ q _What I claim is:

1 . A pharmaceutical (including veterinary) composition for the treatment of calcification, characterised in that it is

(a) either a topically applicable composition, or

2. A composition as claimed in claim 1 , characterised in that it comprises as active agent acetylsalicylic acid either as a free acid or as its alkali metal or ammonium salt or as its ester formed with a lower alkanol or aminoalkanol.

3. A composition as claimed in claim 1 or 2, characterised in that it comprises free acetylsalicylic acid as active agent.

4. A composition as claimed in any of claims 1 to 3, characterised in that it contains, beside the active agent, one or more activity-complementing agent(s), too.

5. A composition as claimed in any of claims 1 to 4, characterised in that it contains 0.1 -20 % by weight, preferably 0.5-15 % by weight, particularly preferably 1-10 % by weight of active agent, calculated for the total weight of the composition.

6. A composition as claimed in any of claims 1 to 5 for topical application, characterised in that it contains as activity-complementing agent(s) one or more antiphlogistic agents, analgesic agents, antirheumatic agents, muscle relaxants, local anaesthetics, pore dilatators, vasopermeability-improving agents, antithrombotic agents and/or agents alleviating skin irritations.

7. A composition as claimed in any of claims 1 to 6 for topical application, characterised in that it contains as activity-complementing agent a pore dilatator and/or a vasopermeability-improving agent in an amount of 0.01-2 % by weight, preferably 0.05-0.5 % by weight, calculated for the total weight of the composition.

8. A composition as claimed in any of claims 1 to 4 in the form of an injectable composition or infusion, characterised in that it contains 0.01-2 % by weight, preferably 0.05-0.5 % by weight of active agent calculated for the total weight of the composition.

9. A composition as claimed in claim 8, characterised in that it also contains one or more activity-complementing agent(s) as listed in claim 6.

10. A composition as claimed in claim 8 or 9, characterised in that it also contains a CO₂-absorbing component.

11. A composition as claimed in any of the preceding claims, characterised in that it contains the active agent in sustained-release form.