RU2179023C2 - Method for treating the cases of chronic polyarthritis - Google Patents

Abstract

FIELD: medicine. SUBSTANCE: method involves administering Prostane derivatives. EFFECT: enhanced effectiveness of in destroying collagenous cartilage fibrils. 8 cl, 14 dwg

Description

 The invention relates to the use of prostane derivatives for the preparation of a medicament for the treatment of an immune response.

European Patent Publication EP-0011591 (filing date October 18, 1979) describes certain prostane derivatives and their preparation. In the case of these derivatives of prostane, we are talking about compounds that are derivatives of prostacyclin (PGl ₂ ). They contain a methylene group instead of the ether oxygen atom at position 9 in prostacyclin. Derivatives of Prostan are used to treat various diseases, and in the first place they have a clear cardiovascular and inhibitory platelet aggregation effect.

 The use of prostane derivatives as a medicine is described in detail in European patent EP-0011591: reduction of peripheral, arterial and coronary vascular resistance; inhibition of platelet aggregation and dissolution of white blood clots; myocardial cytoprotection and thus a decrease in systemic blood pressure without simultaneously reducing systolic blood volume and coronary blood flow; stroke treatment; prevention and therapy of coronary heart diseases, coronary thrombosis, heart infarction, peripheral arterial diseases, arteriosclerosis and thrombosis; shock therapy; inhibition of bronchial compression; inhibition of gastric acid secretion and cytoprotection of the mucous membrane of the stomach and intestines; antiallergic properties; decreased pulmonary vascular resistance and pulmonary blood flow; promoting renal blood flow; use instead of heparin or as an adjuvant in hemofiltration dialysis; preservation of stored blood plasma preparations, especially canned platelets; inhibition of labor pain; treatment of toxicosis during pregnancy; antiproliferative effect; increased cerebral blood flow.

 European patents EP-0056208, EP-0099538 and EP-0119949 specify carbocycline derivatives which have similar indications as the aforementioned prostane derivatives.

 EP-0084856 describes other prostane derivatives that are suitable for use in inhibiting platelet aggregation, reducing systemic blood flow, or treating stomach ulcers. In particular, Beraprost is mentioned there.

 The use of prostane derivatives for the treatment of immune response is described in various publications. So, already in the European patent EP-0011591, by the way (in passing), treatment is mentioned due to anti-allergic properties.

 EP-0055208 describes, among other things, the anti-allergic effect of carbocycline derivatives.

 In the publication of H. J. Grundmann et al. (1992), J. Infect. Dis., 1992, 165, 1-5, describes in detail the use of a prostane derivative, namely Iloprost, in the treatment of septic shock.

 In the international patent application PCT / DE92 / 00100 (the day of filing the substantiating priority of the application on February 12, 1991 in the Federal Republic of Germany), the therapy of AIDS and diabetes using prostane derivatives is mentioned. This application is a prior right.

 A publication by K. Sliwa et al. (1991), Infection and Immunity, 59, 3846-3848, refers to the treatment of cerebral malaria with Iloprost.

 It has now been unexpectedly found that prostane derivatives can be used for another indication.

или общей формулы (II)

где X₁ обозначает -CH₂-CH₂-; транс-CH=CH- или

X₂ обозначает линейную или разветвленную насыщенную алкиленовую группу с 1-6 C-атомами;
X₃ обозначает -O- или -CH₂-;
X₄ обозначает -CH₂- или -(CH₂)₃-;
X₅ обозначает -H или

R₁ обозначает атом водорода, алкильную группу с 1-6 C-атомами, циклоалкильную группу с 5 или 6 C-атомами или фенильную группу;
R₂ обозначает линейную или разветвленную, насыщенную или ненасыщенную алкильную группу с 1-6 C-атомами;
R₃ обозначает атом водорода, ацильный остаток с 1-4 C-атомами или бензоильный остаток; и
R₄ обозначает -H или -CH₃;
причем -O-R₃-группа находится в α- или β-положении, и их солей с физиологически приемлемыми основаниями, если R₁ обозначает атом водорода;
для получения лекарственного средства для лечения хронического полиартрита.The invention relates to the use of prostane derivatives of the general formula (I)

or general formula (II)

where X ₁ is —CH ₂ —CH ₂ -; trans-CH = CH- or

X ₂ denotes a linear or branched saturated alkylene group with 1-6 C-atoms;
X ₃ is —O— or —CH ₂ -;
X ₄ is —CH ₂ - or - (CH ₂ ) ₃ -;
X ₅ is —H or

R ₁ represents a hydrogen atom, an alkyl group with 1-6 C atoms, a cycloalkyl group with 5 or 6 C atoms or a phenyl group;
R ₂ denotes a linear or branched, saturated or unsaturated alkyl group with 1-6 C-atoms;
R ₃ represents a hydrogen atom, an acyl residue with 1-4 C atoms or a benzoyl residue; and
R ₄ is —H or —CH ₃ ;
wherein the —OR ₃ group is in the α or β position, and their salts with physiologically acceptable bases, if R ₁ is a hydrogen atom;
to obtain a drug for the treatment of chronic polyarthritis.

If X ₂ denotes a linear or branched saturated alkylene group with 1-6 C-atoms, then it is, for example, methylene, ethylene, propylene, isopropylene, and the methyl group is bonded to the first or second carbon atom of ethylene, counting from group A; butylene, methylpropylene, ethylene, dimethylethylene, wherein the methyl or ethyl group is in any way linked to the alkylene chain; pentyl, methylbutylene, dimethylpropylene, ethylpropylene, methyl ethyl ethylene, wherein the methyl or ethyl group is in any way linked to the alkylene chain; hexylene, methylpentylene, dimethylbutylene, methylethylpropylene, wherein the methyl or ethyl group is in any way linked to the alkylene chain.

R ₁ in the meaning of an alkyl group covers linear or branched alkyl groups with 1-6 C-atoms, such as, for example, methyl, ethyl, propyl, butyl, isobutyl, tert. -butyl, pentyl, neopentyl, hexyl. The cycloalkyl group R ₁ may contain 5 or 6 C-atoms in the ring.

The alkyl group R ₂ may consist of linear or branched, saturated or unsaturated alkyl residues with 1-6 C atoms, preferably alkyl radicals are saturated. For example, methyl, ethyl, propyl, butyl, isobutyl, tert.-butyl, pentyl, hexyl, butenyl, isobutenyl, propenyl, pentenyl or hexenyl groups are mentioned.

The acyl group R ₃ may be a linear or branched acyl group with 1-4 C atoms, such as, for example, acetyl, propiolinyl, butyryl or isobutyryl.

 The invention also relates to a method for treating chronic polyarthritis in humans and mammals in need of such treatment, the treatment comprising administering a pharmacologically safe and effective amount of a prostane derivative according to formula (I) or formula (II) to humans and mammals.

 Inorganic and organic bases which are known to those skilled in the art for the preparation of physiologically acceptable salts are suitable for salt formation with free acids. For example, alkali metal hydroxides should be mentioned, such as sodium and potassium hydroxide; alkaline earth metal hydroxides, such as calcium hydroxide; ammonia; amines like ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, morpholine, tris (hydroxymethyl) methylamine, etc. Obtaining β-cyclodextrin clathrate (clathrate complex) is carried out according to European patent EP-0259468.

 Chronic polyarthritis is a disease of the joints, and the synovial tissue has a destructive effect on the matrix of articular cartilage. In the synovial tissue and in the synovial fluid of patients with chronic polyarthritis, there are active cells that secrete cytokines like TNF-α and Il-1. Both cytokines, TNF-α and Il-1 are able to induce the production of collagenase and other neutral proteases in synovial fibroblasts and chondrocytes, which are located near the articular cartilage. These enzymes destroy proteoglycans and collagen, which leads to the destruction of cartilage (TNF-α = tumor necrosis factor-α; Il-1 = Interleukin-1).

 Surprisingly, prostane derivatives have proven useful in the treatment of chronic polyarthritis. Until now, substances such as carboxylic acids (salicylates, aryl acetic acids, phenamates, propionic acids), pyrazolones and oxycams (Handbook of Experimental Pharmacoly, 1979, Springer Verlag, T. 50 / II, authors: GVR Born and others Chapter 30, Anti-Inflammatory Drugs, JR Vane, SH Ferreira, Ch. 32, Classification of Antirheumatic Drugs, EC Huskisson, Ch. 37, MK Jasan).

R₁ обозначает атом водорода, алкильную группу с 1-3 C-атомами или фенильную группу,
R₂ обозначает линейную или разветвленную, насыщенную или ненасыщенную алкильную группу с 1-3 C-атомами,
R₃ обозначает атом водорода или ацильный остаток с 2-мя C-атомами, и
R₄ обозначает -H;
причем -O-R₃-группа находится в α- или β-положении, и их солей с физиологически приемлемыми основаниями, если R₁ обозначает атом водорода,
для получения лекарственного средства для лечения хронического полиартрита.Preferably, the prostane derivatives of the aforementioned general formula (I) according to the invention are used, where
X ₁ is trans-CH = CH-;
X ₂ denotes a linear or branched saturated alkylene group with 2-4 C-atoms;
X ₃ is —CH ₂ -;
X ₄ is —CH ₂ -;
X ₅ is

R ₁ denotes a hydrogen atom, an alkyl group with 1-3 C-atoms or a phenyl group,
R ₂ denotes a linear or branched, saturated or unsaturated alkyl group with 1-3 C-atoms,
R ₃ denotes a hydrogen atom or an acyl residue with 2 C-atoms, and
R ₄ is —H;
wherein the —OR ₃ group is in the α or β position, and salts thereof with physiologically acceptable bases, if R ₁ is a hydrogen atom,
to obtain a drug for the treatment of chronic polyarthritis.

R₁ обозначает атом водорода или метильную группу;
R₂ обозначает метильную или этильную группу;
R₃ обозначает атом водорода или формильную группу; и
R₄ обозначает водород,
причем -O-R₃-группа находится в α- или β-положении, и их солей с физиологически приемлемыми основаниями, если R₁ обозначает атом водорода, для получения лекарственного средства для лечения хронического полиатрита.More preferably, the use of the prostane derivatives according to the invention of the aforementioned general formula (I), wherein
X ₁ is trans-CH = CH-;
X ₂ is a methylene group, the methyl group being bonded to the first carbon atom of the ethylene group and the first carbon atom of the ethylene group directed to group A;
X ₃ is —CH ₂ -;
X ₄ is —CH ₂ -;
X ₅ is

R ₁ represents a hydrogen atom or a methyl group;
R ₂ represents a methyl or ethyl group;
R ₃ represents a hydrogen atom or a formyl group; and
R ₄ is hydrogen,
moreover, the —OR ₃ group is in the α or β position, and their salts with physiologically acceptable bases, if R ₁ is a hydrogen atom, to obtain a medicament for the treatment of chronic polyatritis.

R₁ обозначает атом водорода;
R₂ обозначает метильную группу;
R₃ обозначает атом водорода; и
R₄ обозначает водород,
причем -OH-группа находится в α- или β-положении, и его солей с физиологически приемлемыми основаниями, для получения лекарственного средства для лечения хронического полиартрита.Most preferably, the use of the prostane derivative according to the invention of the aforementioned general formula (I), wherein
X ₁ is trans-CH = CH-;
X ₂ is a methylene group, the methyl group being bonded to the first carbon atom of the ethylene group and the first carbon atom of the ethylene group directed to group A;
X ₃ is —CH ₂ -;
X ₄ is —CH ₂ -;
X ₅ is

R ₁ represents a hydrogen atom;
R ₂ is a methyl group;
R ₃ represents a hydrogen atom; and
R ₄ is hydrogen,
moreover, the -OH-group is in the α- or β-position, and its salts with physiologically acceptable bases, to obtain a medicinal product for the treatment of chronic polyarthritis.

 This substance is called Iloprost and is 5- (E) - (1S, 5S, 6R) -7-hydroxy-6 [(E) - (3S, 4RS) -3-hydroxy-4-methyl-1- octen-6-ynyl] bicyclo / 3.3.0 / octen-3-ylidene-pentanoic acid. This substance is the most preferred compound of the present invention.

 Further, the invention encompasses the use of preferred substances, such as Cicaprost (cicaprost), Eptaloprost (eptaloprost): Ciprosten (ciprosten) and / or Beraprost (beraprost), and their soda for the manufacture of a medicament for the treatment of chronic polyarthritis. The structure of the substance, including Iloprost, is presented in table 1.

 The invention further relates to the use of prostane derivatives according to the invention together with pharmacological excipients and carriers that are physiologically acceptable. Such substances are described in Remington's Pharmaceutical Science, 15th ed. Mack Publishing Company, Easton Pennsylvania (1980).

 Methods for preparing certain prostane derivatives according to the invention are described in detail in European patent EP-0011591 or EP-0084856. The substances of formula (I) or formula (II) not specifically mentioned therein, however, do not differ with respect to the preparation method. A specialist can receive them in the framework of the well-known.

 The compounds of general formula (I) or (II) are effectively used in the following test.

 Synovial fluid cells of patients with chronic polyarthritis co-cultivate in vitro with 4-day buds of the extremities (Gliedknospen, limbuds) of mouse embryos (12 days old). After co-cultivation for approximately 7 days, the cartilage in the limbuds is destroyed, which can be reduced in the presence of prostane derivatives according to the invention.

 Cartilage destruction is determined by the release of sulfated glucosaminoglycans, which are quantified as a complex of glucosaminoglycan with alkane blue.

 Prostane derivatives according to the invention reduce the release of glucosaminoglycans, the release being induced through synovial cells.

 Studies using an electron microscope of cartilage, which was exposed to the activated synovial cells of patients with chronic polyarthritis, show the complete destruction of collagen fibrils; in the presence of prostane derivatives according to the invention, the destruction of collagen fibrils is reduced.

 Biochemically and using an electron microscope, the test system studied shows that cartilage destruction induced by the synovial cells of patients with chronic polyarthritis is reduced due to the prostane derivative of formula (I) or formula (II) proposed according to the invention.

 Prostane derivatives according to the invention are effective in the above test at concentrations of 0.1-1000 ng / ml. The above in vitro test system is transferred to in vivo processes (see: JJ Steinberd et al. (1983), Biochem. Biophys. Acta, 757, 47-58; hereinafter MJ Grossley and IMHunneyball (1984), Biochem. Pharmac. 33, 1263-1271; further, K. Keller et al. (1990), J. Orthop. Res, 8, 345-352). An in vitro system of this kind is complex, it is representative of the picture of the disease in chronic polyarthritis.

 Compounds of general formula (I) or (II) are useful in the treatment of chronic polyarthritis.

 For this therapeutic effect, the required dose is different and depends, for example, on the compound of the general formula (I) or (II) of the “host” used, the route of administration and the nature and severity of the condition being treated. In general, however, in the case of animals, satisfactory results should be expected with daily doses of 1-3000 μg / kg body weight. In the case of large mammals, for example humans, the recommended daily dose is 0.1-200 mg of the prostane derivatives of the general formula (I) or (II) according to the invention. Amounts of 0.3-60 mg per day are preferred, more preferably 1-20 mg per day, and most preferably 2-10 mg per day. The daily dose of prostane derivatives can more conveniently be administered in the form of 2-4-partial doses per day.

 Prostane derivatives of the general formula (I) or (II) for systemic treatment can be administered by any conventional route, in particular intestinal, preferably oral, preferably parenteral. Suitable administration forms are suppositories, tablets, capsules, drops, injectable solutions or suspensions.

 The prostane derivative Iloprost is a particularly preferred substance. It is administered, for example, to larger mammals, for example humans, in the above form. In this case, the dose is half as much as the above. The preferred form of administration for systemic treatment is an intravenous solution in the form of continuous infusion in conventional aqueous solvents, for example, as a physiological solution of sodium chloride. From 0.01 ng / kg / min to 1.0 ng / kg / min, preferably 0.03-0.3 ng / kg / min, and most preferably 0.1 ± 0.05 ng / kg / min

 Since chronic polyarthritis also manifests itself in jerky seizures, the prostane derivative according to the invention also needs to be administered over time without symptoms. Thus, the prostane derivative according to the invention serves for prophylaxis. Doses during prophylactic administration do not significantly deviate from the above doses, however, amounts that are 2-4 times less than those used for acute attacks are preferred.

 The present invention also relates to therapeutic compositions which comprise a prostane derivative of the general formula (I) or (II) together with at least one pharmaceutical carrier, additive or diluent, which are all physiologically acceptable. Such compositions may be prepared per se in a known manner. Pharmacologically acceptable and suitable adjuvants and carriers are described, for example, in Remington's Pharmaceutical Science, 15th ed. Mack Publishing Comp., Easton Pennsylvania (1990). It is also possible to use cyclodextrin clathrates, which are indicated in European patent application EP-0259468.

 Compared with systemic treatment, the local use of the prostane derivative according to the invention is particularly preferred, if necessary together with adjuvants and / or carriers.

 At higher concentrations of prostane derivatives in the blood, they increase the cardiovascular effect. Therefore, it is preferable that the prostane derivatives according to the invention are applied directly to the skin of a damaged joint. Ointments, pastes, gels or packaging are suitable for this purpose. This listing is inconclusive.

 Due to local application, a high concentration of prostane derivatives is preferably applied to the corresponding joint, and at the same time, the concentration of prostane derivatives in the blood is practically below the detection limit. The high bioavailability of prostane derivatives leads to rapid penetration through the skin and underlying connective tissue, and the distribution of prostane derivatives occurs according to the law of diffusion. In contrast, convection conveying plays a completely unsatisfactory role. Vessels that are in or under the skin coated with prostane derivatives are either too small (venoles, arterioles), or have a too small effective surface (veins, arteries) on the skin to cause a noticeable concentration of prostane derivatives in the blood.

Example 1. Cell culture from synovial fluid
Cells from the synovial fluid of patients with chronic polyarthritis co-cultivate in vitro along with 4-day primordia of limbs (limbuds) of mouse embryos (at the age of 12 days). After co-cultivation for approximately 7 days, cartilage in the limbuds is destroyed, which can decrease in the presence of prostane derivatives according to the invention.

 The substance Iloprost is in a final concentration of 100 ng / ml of culture medium in cell cultures and is added at the beginning of the test to cell cultures. Samples are taken on days 1-7. Cultivation conditions are described in detail in: H. Mohamed-Ali (1991), J. Rheumatol. 50, 74-81; further H.J. Merker (1991), in Culture Techneques; D. Neubert and H.J. Merker (authors), Valter de Gruyter Verlag. Berlin - New-York, S.S. 119-133; further H.B. Fell and R.W. Jubb (1977), Arthritis Rheuma, 20, 1359-1371.

 The control mixture instead of Iloprost contains only a nutrient medium.

Example 2. Determination of cartilage destruction
Cartilage destruction is determined by the release of sulfated glucosaminoglycans, which are measured quantitatively as a complex of glucosaminoglycan with alkane blue. The release of glucose aminoglycan is described by P. Whiteman (1973), Biochem. J. 131, 343-351. Samples taken on days 1-7 show the results listed in table 2.

 Prostane derivatives according to the invention significantly reduce the release of glucosaminoglycans.

Example 3. Evaluation using an electron microscope
Studies using an electron microscope of cartilage, which was exposed to activated synovial cells in patients with chronic polyarthritis, show the complete destruction of collagen fibrils. In the presence of prostane derivatives according to the invention, the destruction of collagen fibrils is reduced.

 The preparation of electron microscopy preparations and histological evaluation are described in: H. Mohamed-Ali (1991), J. Rheumatol. 50, 74-81; further H.J. Merker (1991), in Culture Techniques, D. Neubert and H.J. Merker (authors) Walter de Gruyter Verlag, Berlin - New York, S.S. 119-133, hereinafter referred to as H.B. Fell and R. W. Jubb (1977), Arthritis Rheuma, 20, 1359-1371. Treated according to the invention derived prostane cell culture from patients with chronic polyarthritis are, according to their clinical picture, between cells from patients with chronic polyarthritis without treatment derived prostane and cells from patients without chronic polyarthritis. Collagen degradation reduction is estimated on the basis of drugs up to 50%.

Claims (9)

1. The use of derivatives of prostane of General formula I

or general formula II

where X ₁ is —CH ₂ —CH ₂ -, trans —CH = CH— or

X ₂ denotes a linear or branched saturated alkylene group with 1-6 C-atoms;
X ₃ is —O— or —CH ₂ -;
X ₄ is —CH ₂ - or - (CH ₂ ) ₃ -;
X ₅ is —H or —C

C-R ₂ ;
R ₁ represents a hydrogen atom, an alkyl group with 1-6 C atoms, a cycloalkyl group with 5 or 6 C atoms or a phenyl group;
R ₂ denotes a linear or branched, saturated or unsaturated alkyl group with 1-6 C-atoms;
R ₃ denotes a hydrogen atom, an acyl residue with 1-4 C-atoms or a benzoyl residue;
R ₄ is —H or —CH ₃ ;
wherein the —O — R ₃ - group is in the α or β position, with the exception of compounds of general formula II, wherein R ₁ is a phenyl group;
R ₃ is an acyl residue; R ₄ is —CH ₃ ;
X ₁ is

;
X ₄ is - (CH ₂ ) ₃ ,
and salts thereof with physiologically acceptable bases, if R ₁ is a hydrogen atom, as an active substance in the manufacture of a medicament for the treatment of chronic polyarthritis. 2. The use of prostane derivatives according to claim 1 of general formula I, wherein X ₁ is trans-CH = CH-; X ₂ denotes a linear or branched saturated alkylene group with 2-4 C-atoms; X ₃ is —CH ₂ -; X ₄ is —CH ₂ -; X ₅ is

R ₁ denotes a hydrogen atom, an alkyl group with 1-3 C-atoms or a phenyl group; R ₂ denotes a linear or branched, saturated or unsaturated alkyl group with 1-3 C-atoms; R ₃ represents a hydrogen atom, an acyl residue with 2 C atoms; R ₄ is —H, wherein the —O — R ₃ group is in the α or β position, with the exception of compounds of the general formula II, where R ₁ is a phenyl group, R ₃ is an acyl radical, R ₄ is —CH ₃ , X ₁ stands for

and X ₄ is - (CH ₂ ) ₃ , and their salts with physiologically acceptable bases, if R ₁ is a hydrogen atom, as an active substance in the manufacture of a medicament for the treatment of chronic polyarthritis. 3. The use of prostane derivatives according to claim 2 of general formula I, wherein X ₁ is trans-CH = CH-; X ₂ is a methylene group, the methyl group being bonded to the first carbon atom of the ethylene group and the first carbon atom of the ethylene group directed to group A; X ₃ is —CH ₂ -; X ₄ is —CH ₂ -; X ₅ is

R ₁ represents a hydrogen atom or a methyl group; R ₂ represents a methyl or ethyl group; R ₃ represents a hydrogen atom or a formyl radical; R ₄ is —H; wherein the —O — R ₃ - group is in the α- or β-position, with the exception of compounds of general formula II, where R ₁ is a phenyl group, R ₃ is an acyl residue, R ₄ is —CH ₃ , X ₁ is

and X ₄ is - (CH ₂ ) ₃ , and their salts with physiologically acceptable bases, if R ₁ is a hydrogen atom, as an active substance in the manufacture of a medicament for the treatment of chronic polyarthritis. 4. The use of prostane derivatives according to claim 3 of general formula I, wherein X ₁ is trans-CH = CH-; X ₂ is a methylene group, the methyl group being bonded to the first carbon atom of the ethylene group and the first carbon atom of the ethylene group directed to group A; X ₃ is —CH ₂ -; X ₄ is —CH ₂ -; X ₅ is

R ₁ represents a hydrogen atom; R ₂ is a methyl group; R ₃ represents a hydrogen atom; R ₄ is —H, wherein the OH group is in the α or β position, with the exception of compounds of the general formula II, where R ₁ is a phenyl group, R ₃ is an acyl radical, R ₄ is —CH ₃ , X ₁ is

and X ₄ is - (CH ₂ ) ₃ , and their salts with physiologically acceptable bases as the active substance in the manufacture of a medicament for the treatment of chronic polyarthritis.  5. The use of the prostane derivative according to claim 1, which is Cicaprost (cicaprost), and its salts as an active substance in the manufacture of a medicament for the treatment of chronic polyarthritis.  6. The use of the prostane derivative according to claim 1, which is Eptaloprost (eptaloprost), and its salts as an active substance in the manufacture of a medicament for the treatment of chronic polyarthritis.  7. The use of the prostane derivative according to claim 1, which is Ciprosten (ciprosten), and its salts as an active substance in the manufacture of a medicament for the treatment of chronic polyarthritis.  8. The use of the prostane derivative according to claim 1, which is Beraprost (beraprost), and its salts as an active substance in the manufacture of a medicament for the treatment of chronic polyarthritis.  9. The use of a derivative of Prostan according to paragraphs. 1-8 together with physiologically acceptable carriers and excipients.

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