MEDICINAL COMPOSITION AND METHOD FOR THE TREATMENT OF PERIARTHRITIS AND SIMILAR DISEASES

Abstract: Medicinal compositions suitable for the treatment, by means of ionophoretic or similar techniques, mesotherapy or endoarticular infiltrations, of periarthritis or similar affections including one or more calcium-complexing compounds such as alkylene- or oxyalkylene-diamino polyalkanoic acids or diphosphonic acids and an aqueous carrier preferably containing an enzyme endowed with anti-inflammatory activity. The invention has the advantage of a remarkable effectiveness without dangerous systemic side-effects.

Description: MEDICINAL COMPOSITION AND METHOD FOR THE TREATMENT OF PERIARTHRITIS AND SIMILAR DISEASES Object of the present invention is a medicinal composition with calcium-complexing and antiinfla matory activity, and a method for the treatment of periarthritis and similar affections, by means of ionophoretic treat- ments or therapeutically equivalent treatments (mesothera- py, endoarticular infiltrations etc.). It is well-known that periarthritis and similar affections, such as abarticular rheumatisms in general, dismetabolic rheumatisms and rheumatoid arthritis, are often associated with calcium salts deposits in correspon¬ dence of the ligaments of the affected articulations, and that the presence of these deposits, that act as inflamma¬ tory agents, often neutralizes, or reduces, the effect of the systemic or topical treatments carried out by means of antiinflammatory drugs, and that it may also bring about relapses even in the case that these treatments had a temporary positive effect. On the other hand, it is a common opinion that, if these calcareous deposits could be removed, many periarthritis and similar affections could be easily treated by the antiinflammatory drugs, and some of them would even spontaneously regress. At present, the treatment of periarthritis and of similar affections, besides being based on pharmacological antiinflammatory treatments, especially on physical treat- ments (exercise, manipulations, massages, tractions, elec¬ tromagnetic infrared, visible, ultra-violet or rδntgen radiations, electromagnetic inductions, ultrasound appli- cations and so on), the essential effect thereof is to activate locally blood circulation with the purpose of solving the calcareous deposits, even though this purpose is hardly reached. However, up to now no drug was available that could allow to act directly and effectively destroying or redu¬ cing these calcareous deposits. There exist well-known drugs for sistemic use, able to reduce calcemia and as a consequence, theoretically able to create a trend towards the dissolution of calcareous deposits, but, especially due to the low solubility of said deposits, their effect to this extent would be extremely low and would take place only with dosages able to bring about a strong, systemic hypocalcemia, that would be intolerable to keep for a long time in the whole body. On the other hand, these drugs are not suitable for a topical use because they are not absor¬ bed in sufficient quantities, and, above all, they cannot reach in effective concentrations the localizations, that are not superficial, yet sometimes they are very deep, of the calcareous deposits that should be attacked. The present invention concerns a calcium-complex and antiinflammatory medicinal composition, for the treat¬ ment of periarthritis and of similar affections, which composition is introduced in body in order to reach in effective concentrations the sites where the calcareous deposits to be attacked are located, without changing to a relevant extent the organism systemic calcemia, so that it is possible to reduce, and even to demolish completely the calcareous deposits connected with a periarthritis or a similar affection, carrying out at the same time a suita- ble antiinflammatory local treatment. To achieve this aim, the invention uses, for the introduction of the drug, ionophoresis, mesotherapy, or endoarticular infiltrations or therapeutically equivalent techniques that, if suitably carried out, allow to carry to pre-established sites in the body effective quantities of active substances, avoid¬ ing their systemic diffusion in high concentrations; thus also avoiding the negative side-effects that would be present administering the same composition by systemic or topical route. The pharmaceutical composition according to the invention comprises: a) one or more calcium-complexing compounds of the group of alkylene- or oxyalkylene-diamino-polyalkanoic acids or of the group of diphosphonic acids; b) a carrier suitable for ionophoretic or similar uses. Examples of diphosphonic acids which may be compri¬ sed in the pharmaceutical compositions according to the present invention are chlodronic acid, amino-hydroxypropa- ne diphosphonic acid, etc. Alkylene- or oxyalkylene-diamino-polyalkanoic acids suitable for the pharmaceutical compositions of the inven¬ tion may be represented by the following general formula: wherein: A represents an alkylene or oxyalkylene group; R represents hydrogen, a carboxymethyl or carboxy (hydro- xyphenyl) methyl group; R may have the same meanings as R groups, with the pro¬ viso that when R groups are hydrogen, R groups are different from hydrogen, and viceversa. Examples of alkylene groups are ethylene or propyl- ene groups. Example of oxyalkylene groups is the ethylene bis(oxyethylene) group. Examples of compounds of formula (I) are: - glycoletherdiaminotetraacetic acid (GETA); - ethylenediaminotetraacetic acid (EDTA); - diethylenetriaminopentaacetic acid (DTPA or DPTA) ; - trans-1,2-diaminocyclohexane-N,N,N' ,N' -tetraacetic acid (CDTA or DCTA) ; - ethyleneglycole-2-(2-aminoethyle)-tetraacetic acid (EGTA) . Besides the compounds represented by the above general formula and salts thereof, other calcium-complex¬ ing compounds, such as diethylenetriamino pentaacetic acid, nitrilotriacetic acid (NTA) etc. may be used. Among compounds of general formula (I) , ethylene- diaminotetraacetic acid (EDTA) proved to be particularly effective, preferably when salified in form of calcium disodium salt, which has the advantage of further reducing the hypocalcemia risk. Other suitable EDTA salts according to the inven- tion are: dipotassium, tripotassium, disodium, trisodium, tetrasodium and diammonium salts; litium double salt; monosodium ferric salt; disodium mixed salts with copper, magnesium or zink. According to the invention, particularly preferred is the edetic acid disodium salts, also known as disodium tetracemate, having the following formula: This substance is endowed with a strong hypocalce- mic effect and at present it is used for intravenous injections to decrease calcium systemic level in blood in hypercalcemia, especially in children and breast-fed ba¬ bies, and to prevent problems during massive blood tran- sfusions. This substance turns out to be ionizable, giving origin to an edetic acid anion and two sodium cations, so that, if submitted to an electric field, it gives origin to a migration of edetic acid (its therapeutically effec- tive component) to the anode. In the tests carried out in the development of the present invention, the disodium salt of edetic acid was specifically used. This salt is marketed in France under the name of "Tetracemate disodique (R)". Another similar product, that might be used according to the invention, is sodium edetate calcium, marketed in France under the name (R) "Calcitetracemate disodique ". The carrier used according to the invention is an aqueous carrier compatible with ionophoresis, mesotherapic techniques or with endoarticular infiltrations, and it is preferably an aqueous solution or suspension of antiin- flammatory and antiphlogistic activity enzyme proteins. Said enzymes, mainly belonging to the 3 group of enzymes classification (hydrolase), and particularly to 3.2 sub- group (enzymes active on glucoside compounds), include for example mucopolysaccharidase, (X-chymotrypsin, hyaluroni- dase, bromelain, α-amilase, papain, streptokinase - streptodornase and the like. In particular, tests with Q t-chymotrypsin were carried out, using the product marketed in France under the name "Alphachymotrypsine Choay lyophilisee (R)", and with testicular mucopolysaccharidase (this product is marketed in France under the name of "Thiomucase (R)"), and good results were obtained, especially with the latter product. Due to the absence of systemic effects in the pre¬ sent invention, the quantitative composition of the compo¬ sitions is not particularly critical and it may vary within wide limits, according to the pathology to be trea- ted and to the chosen treatment technique. A preferred composition, that turned out to be particularly suitable to the scope of the invention, in¬ cludes 2.5 ml of a 5% aqueous solution of disodium salt of edetic acid and of 100 TRU of testicular mucopolysaccharidase ("Thiomucase (R)"). In order to carry out the treatment, an ionophore- sis apparatus equipped with potentiometric regulation was used. By means of the potentiometric regulation, a light current was maintained, the intensity of which ranged from 1 to 3 mA (the preferred value being 2 mA) , and its dura¬ tion ranged from 15 to 30 minutes (the preferred value being between 20 and 25 minutes), applying the negative pole to the buffer containing the active substance. These ionophoretic treatments are to be repeated as many times as it is necessary according to the situation, generally from 15 to 30 times, at a distance of time ranging from 2 to 10 days, preferably as often as 2-3 days a week. In order to carry out this treatment, the negative electrode must be accurately placed in correspondence of the calcification, that is generally detected and located by X-rays, whereas the positive electrode is placed in a suitable position facing the negative electrode. Several cases were treated with this therapeutic scheme and with the preferred composition reported above, and favourable and advantageous results were obtained. In particular, it has been found that the ionopho- resis treatment of periarthritis and similar affections allows a strong reduction both of pain and of the calcifi¬ cation connected with the affection in a reasonably short time, as it was ascertained by X-rays. The treatment of the invention, due to its local character, does not change the body systemic conditions and it can also by used with¬ out dangers in particular sensitive or intolerant sub¬ jects. Even though in what said above the use of the medi¬ cinal compound according to the invention in a therapeutic method based on ionophoretic treatments was particularly pointed out, it must be known that the composition may also be used in treatments of a different kind, provided that they are substantially equivalent, from a therapeu¬ tic point of view, to the ionophoretic, mesotherapic and infiltrative treatments.

Claims: CLAIMS 1. Medicinal compositions suitable for the treatment, by ionophoretic, mesotherapic, infiltrative or similar techniques, of periarthritis or similar affections, inclu¬ ding one or more calcium-complexing compounds selected in the group of alkylene- or oxyalkylene-diamino-polyalkanoic acids, or diphosphonic acids, in admixture with a suitable aqueous carrier. 2. Compositions according to claim 1, characterized in that they contain as calcium-complexing compound a compo¬ und of formula: wherein: A represents an alkylene or oxyalkylene group; R represents hydrogen, a carboxymethyl or carboxy (hydro- xyphenyl) methyl group; R has the same meanings as R with the proviso that when R is hydrogen, R is different from hydrogen, and viceversa, and sodium, potassium, lithium, ammonium, calcium salts thereof and mixed salts thereof of sodium with iron, cop¬ per, magnesium, zinc. 3. Compositions according to claim 1, characterized in that the calcium-complexing compound is ethylenediaminote- traacetic acid and disodium, disodium-calcium, trisodium, tetrasodium, dipotassium, tripotassium, diammonium, dili- thium, ferric monosodic salts thereof, disodium salts thereof mixed with copper, magnesium, zinc or cadmium. 4. Compositions according to claim 3 characterized in that the calcium-complexing compound is the ethylenediami- notetraacetic acid disodium salt. 5. Compositions according to any of the previous clai¬ ms, characterized in that the aqueous carrier is an aque¬ ous solution or suspension of an enzyme belonging to the ,rd 3 group. 6. Compositions according to claim 5, characterized in that the enzyme is chosen in the group formed by -chy- motrypsin, mucopolysaccharidase, bromelain, hyaluronidase, -amilase, papain, streptokinase-streptodorr\ se. 7. Compositions according to claim 6, characterized in that the enzyme is Q[-chymotrypsin or testicular mucopoly¬ saccharidase. 8. A composition according to claim 1, consisting of an aqueous solution of ethylenediaminotetraacetic acid disodium salt and of a carrier consisting of a testicular mucopolysaccharidase aqueous solution. 9. A composition according to claim 8, consisting of 2..5 ml of 5% aqueous solution of ethylenediaminotetraace¬ tic disodium salt and of 100 TRU of mucopolysaccharidase. 10. A method for the treatment of periarthritis and similar affections by means of ionophoretic or mesothera¬ pic application or endoarticular infiltration or analo¬ gous techniques of the compositions of claims 1-9.

Inventors: GUAZZOTTI LIVIO, GUAZZOTTI, LIVIO
Applicants: X RAY HOLDING, X-RAY HOLDING S.A.
Application year: 1985
Main classification: A61K37
IPC codes: A61K38