HU182920B - Process for preparing stable pharmaceutical compositions containing cyclosporin - Google Patents

Abstract

The invention relates to novel pharmaceutical administration forms and compositions for the antibiotic S7481/F-1 of the formula <IMAGE> which consist of the compound of the formula I and a) sesame oil and/or b) non-ionic surfactants and/or c) transesterified non-ionic triglycerides and/or d) a mixture consisting of one or more lecithins, transesterified non-ionic triglycerides or ethyl oleate and/or e) a neutral oil and can be administered as a beverage solution, beverage emulsion or injection solution.

Description

The present invention relates to pharmaceutical compositions and compositions containing pharmacodynamically active monocyclic polypeptides, cyclosporins.

Due to their hydrophobic and / or lipophilic nature, ciclosporins exhibit unsatisfactory behavior in their pharmaceutical formulations with solid or liquid pharmaceutical carriers. For example, cyclosporins are not sufficiently resorbed from such formulations, or the formulations are poorly tolerated by patients, or are not sufficiently stable during storage; for example, the concentration of ciclosporin crystallizes and / or the concentration of ciclosporin can be kept in solution without crystallization, for example in the order of 3% or less.

Such difficulties occur not only in liquid but also in solid preparations, such as so-called solid solutions, which can be prepared, for example, by melting a solid carrier, mixing the active ingredient and cooling the mixture: pellets for oral administration.

Although many suggestions for overcoming the above problems have become known, accurate studies have shown that many of these suggestions do not apply to monocyclic peptides, particularly cyclosporins.

Surprisingly, it has now been found that, by using specific ingredients, the above difficulties can be avoided and instability difficulties can be solved.

FIELD OF THE INVENTION The present invention relates to pharmaceutical compositions comprising cyclosporin and a carrier which comprises 10 parts by weight of 0.2-10 parts by weight of cyclosporin, mixed with 2 parts by weight of a natural oil transesterification product with 200 parts to 800 parts by weight of polyethylene glycol, ethanol and a vegetable oil. calculated.

The pharmaceutical compositions of the present invention are suitable for the administration of hydrophobic and / or lipophilic cyclosporins insoluble or poorly soluble in standard pharmaceutical carriers, in particular cyclosporins having the ring structure of formula I, wherein A is a divalent moiety containing linked amino acids (e.g. cyclosporin D); [b] (dihydro-cyclosporin D); [c] (isocyclosporin D); [d] (cyclosporin A) or [e] (dihydrocyclosporin C). Cyclosporin A, dihydrocyclosporin C and isocyclosporin D peptides are preferably processed according to the invention.

The transesterification product of natural oil with polyethylene glycol may be prepared in a known manner, for example, as described in U.S. Patent No. 3,288,824. The esters may be a transesterification product of two molar amounts of a natural oil, such as corn oil, almond oil, peanut oil, olive oil and / or palm oil, in a molar amount of 200 to 800 molecular weight polyethylene glycol. Such esters are prepared, for example, by foot. It is marketed by Gattefosse, Boulogne-sur-Seine, France as LABRAFIL (Fiedler, Lexikon dér Hilfsstoffe, 320, 1971). The preferred ester is prepared from an unsaturated natural oil; preferred is, for example, a mixture of triglycerol oleate polyethylene commercially available as LABRAFIL M 1944 CS.

If any of the ingredients are in a solid state, they should be selected to melt at a temperature at which the peptide is stable.

The concentration and weight ratio of the transesterification product in the pharmaceutical compositions of the present invention will depend, inter alia, on the component used, in particular its solubility, the concentration of ciclosporin used, its concentration in the final formulation and the solubility of any other pharmacological excipients present. The weight ratio of the transesterification product to cyclosporin is 10: 0.2 to 10, preferably 10: 1 to 10, preferably 10: 1 to 7.

For the preparation of the pharmaceutical compositions of the present invention, cyclosporin is admixed with the indicated ingredients. When a component is solid at room temperature, it is heated to 70 ° C to form a liquid melt in which the active ingredient can be dissolved. The combination is then cooled and ground, for example.

The pharmaceutical compositions may be supplemented with other pharmacologically tolerable additives in any known manner suitable for oral or parenteral administration, but the liquid form is preferred.

Preferred pharmaceutical compositions include:

(a) drinking solutions,

(b) drinking emulsions,

(c) injection solutions,

(d) solutions enclosed in a capsule.

The intramuscular or subcutaneous route, preferably the oral route, is preferred.

Up to 60% of the total composition may be added to ethanol. The amount of ethanol, for example, may be 2-5% by weight of the total weight of the combination in parenteral and 1-20% by weight of the oral combination.

The vegetable oil, for example olive oil or corn oil, may be used in an amount of 35-60% by weight of the total composition.

Drinking emulsions may contain from 20 to 80% by weight of water and ethanol.

The properties of the compositions of the invention can be determined by known means. The stability of the solutions, in particular against the crystallization of the active substance, can be determined by known tests. The tolerability of the injectable formulation can be determined by monitoring post-injection hemorrhage and inflammation in the thighs of rabbits and rhesus monkeys, and determining the time needed for their healing, or other known assays can be used to determine tolerability.

Absorption of ciclosporins, in particular the rapid onset of a satisfactory concentration of ciclosporin in the blood and high total peptide absorption over 24 hours can be determined by standard experiments.

In one study, a combination of the invention was administered orally, intramuscularly, or subcutaneously to rabbits, rats, dogs, or rhesus monkeys in an amount of 2 to 600 mg of active peptide per kg body weight. Blood serum and urine samples were taken at regular intervals, such as every hour, and the peptide concentration was determined in a known manner.

The pharmacodynamic activity of the polypeptide can be determined in a known manner. In the case of ciclosporin A, the effect of the peptide can be detected by inhibiting lymphocyte proliferation.

-2182,920

For this purpose, blood serum taken at regular intervals after administration of the test substance is collected and added at a concentration of 0.3-10% in vitro to a mouse spleen cell suspension in which lymphocyte proliferation is induced by treatment with concavallin A for 72 hours. ³ H-thymidine is then added and thymidine incorporation is measured after 24 hours to determine lymphocyte proliferation.

If desired, the peptide may be administered in radioactive form. For cyclosporins such as cyclosporine A labeled pharmaceutical composition of this invention, 100 mg of ³ H-mal (made of Tolypocladium inflatum Gams strain NRRL 8044 known fungal strains fermentation methionine SCH ₃ groups tritiated in the presence of) a drink solution form or capsules, orally or in the form of injection solutions intramuscularly male beaglekutyáknak we entered. Blood samples and urine samples were collected from each animal for 15 minutes to 1 hour after administration, and every hour for 8 hours after administration. Measurement of radioactivity in blood and urine results in peptide absorption values.

The amount of peptide to be administered in the pharmaceutical composition of the invention will, of course, depend on the mode of administration, the desired effect and the treatment conditions.

Generally, the amount of peptide administered in the pharmaceutical composition of the invention will be of the same order of magnitude as the peptide administered by other means.

In the case of ciclosporins, the amount required to achieve the therapeutic effect is known. Using the pharmaceutical compositions of the invention, 3-5 mg / kg of ciclosporin should be administered daily for the treatment of chronic inflammation and for immunosuppressive effects.

The following examples illustrate the invention. Temperature data is given in ° C.

Example 1

drinking solution

LABRAF1L M 1944 CS: ethanol (40:15) in 1 ml was stirred at 25 ° C for 200 mg cyclosporin A; 0.4 ml of olive or corn oil was added and the resulting solution was filtered and bottled.

The solution contains 10 parts by weight of LABRAFIL, 3 parts by weight of cyclosporin A, 3 parts by weight of ethanol and 5 parts by weight of olive or corn oil.

Example 2

Parenteral Formulation For intramuscular and subcutaneous administration, a mixture of mg ethanol and 300 mg LABRAFIL M 1944 CS is mixed with 100 mg cyclosporin A at 25 ° C and made up to 1 ml with olive oil. The solution is aseptically filled into ampoules.

Example 3

Parenteral Formulation For intramuscular and subcutaneous administration, 200 mg of cyclosporin A are dissolved in a mixture of mg ethanol and 300 mg LABRAFIL M 1944 CS at 25 ° C with stirring and the resulting solution is made up to 1 ml with corn oil. Aseptically filled into ampoules.

Comparative studies

Prepared preparations

Formulation I: prepared according to the invention.

The formulation was prepared commercially from the following amounts of ingredients.

component Quantity (kg) i) Labrafil M 1944 CS 150.00 (ii) anhydrous ethanol 50.00 iiia) cyclosporin A-1. dose 9.08 (iiib) cyclosporin A-2. dose 14,23 iiic) cyclosporin A-3. dose 14.00 iiid) cyclosporin A-4. dose 13.30 (iv) olive oil: 212.00 altogether: 462.50 Cyclosporin A [IIIa] -ylid] is complete 50.61

kg, with a defined total water content of 0.61 kg, giving a dry amount of cyclosporin A of 50.0 kg.

All ingredients were added directly to the mixing vessel. First, components i) and ii) were added to the vessel and stirred for 5 minutes. Subsequently, the ingredient IIIa-IIIid) was added in the specified portions while stirring until complete dissolution (about 40 minutes). Compound (iv) was then added with stirring for 10 minutes. The resulting light yellow oily solution was filtered at 0.6-0.8 bar (Gelman Preflow Filter 400-10 μιη) and filled into 50 mL Rexo flasks (51.5 mL = 47.6 g). The bottles were sealed with a rubber stopper and an aluminum cap. All operations were carried out under anhydrous conditions at room temperature and under nitrogen (0.25 bar).

The contents of the bottled solution are as follows for 1 ml.

i) 300 mg / ml Labrafil M 1944 CS;

ii) 100 mg / ml anhydrous ethanol;

iii) 100 mg / ml cyclosporin A (dry weight) and iv) ca. 425 mg / ml olive oil.

// - Comparative preparation V.

The formulations were prepared from the indicated amounts of the following ingredients.

component II Preparation (mg / ml) III IV V i) Labrafil M 194 CS 300 500 700 -737 (ii) anhydrous ethanol - - 100 iii) Ciclosporin A * 100 100 100 100 (iv) olive oil ~ S41 -346 -149 -

* dry weight.

II-V. Formulations were prepared in an analogous manner to Preparation I, but omitted in laboratory size and either Ethanol (Formulation II-IV) or Component (iv) (Formulation V) used as Component (ii).

In formulations II-V, the amount of cyclosporin A per ml was the same as formulation I, the final 100

The dry weight required for -3182 920 mg / ml was determined based on the water content of the feedstock.

Comparative preparation II contained the same amount of Labrafil M 1944 CS as preparation I, but the amount of olive oil present was increased so that the final volume of all solvents was equal to composition I based on 10 mg cyclosporin A (dry weight).

In formulations AIII and IV, the amount of Labrafil M 1944 CS used was increased relative to formulation I, and the amount of olive oil was reduced sufficiently so that the final volume of solvent, calculated per 100 ml of cyclosporin A (dry weight), was the same.

Formulation V contained the same amount of ethanol as formulation I, and Labrafil M 1944 CS was added to achieve the desired final solvent volume.

For the preparation of formulations II-IV, component iii) was added portionwise to component i) with continuous stirring while heating the mixture to dissolve cyclosporin A. Component iv) was then added to the solution in the amount required for the desired final volume. Formulation V was prepared by dissolving component iii) in a mixture of component ii) and i). Formulations II-V were filtered in the same manner as Composition I.

The formulations were filled into ampoules and sealed. All operations were also carried out under anhydrous conditions at room temperature and under nitrogen. Four to four ampoules were used for each assay.

Test method

Bottles containing Formulation I and ampoules containing Formulations II to V were sealed immediately at 5 ° C, room temperature, 25 ° C and 50 ° C. Stored formulations were tested at day 14 and monthly for cyclosporin A precipitated from solution. The precipitation, which appeared as clouding of the solution and sedimentation at the bottom of the container, was determined by simple visual examination.

The results are shown in the following table.

Spreadsheet

Time Temperature I II 14 days I 1 month Preparation II III IV V 2 months 7 months Two years I I V III ARC V I * 5 ° C 1 1 2 3 1 1 3 3 1 1 3 1 1 room temperature 1 3 2 1 1 1 - 3 3 1 1 1 1 1 1 35 ° C 1 3 3 3 1 1 _ _ - 1 1 1 1 1 1 50 ° C 1 3 3 3 1 1 - - - 1 1 1 1 1 * 1

= the solution is clear and no cyclosporin precipitation occurs;

= poor ciclosporin deposition;

= strong cyclosporine precipitation, further observation discontinued;

1 * = slight turbidity due to oxidation of the olive oil component, no ciclosporin precipitation is detected;

V ** = Observation of formulation V was completed after 7 months.

Formulation I according to the invention was stable at all temperatures for at least two years, and cyclosporin A was not produced. Some turbidity was observed after 2 years of storage at 50 ° C, but this is due to the oxidation of the olive oil component and not to the precipitation of cyclosporin A.

Formulations II-IV containing cyclosporin A in an equivalent amount of formulation I, without ethanol, were substantially less stable at all temperatures tested. In most cases, ciclosporin A is vigorously precipitated as early as 14 days and in all cases vigorous precipitation can be observed after 1 month. Comparative preparation V, containing an equivalent amount of solvent I, containing no olive oil, was stable at room temperature to 50 ° C for at least 7 months (after which the formulation was discontinued). However, when stored at 5 ° C, formulation V, although not cyclosporin A precipitated within 1 month, was unstable at 2 months after storage; After 2 months, strong cyclosporine A precipitation was observed.

Comparative formulations II-IV showed poor storage capacity at all test temperatures; thus, they are unsuitable for practical purposes, hospital storage and storage.

Although Comparative Product V may be stored for at least 7 months at room temperature and 50 ° C, storage at 5 ° C is limited to 1 to 2 months.

It is well known that pharmaceutical compositions, for example in hospitals, are usually stored in a cool place (i.e., around 5 ° C) to prevent decomposition of the active ingredient, so that limited storage at this temperature significantly reduces the practical use of the composition.

Surprisingly, formulation I containing components i), ii) and iv) is surprisingly significantly more stable than formulations II-V, which lacked one of components ii) and iv). Formulation I is stable at all temperatures and cyclosporin A does not precipitate, even at 5 ° C, for two years.

Formulation I, with its excellent storage characteristics, 4182,920, is more suitable for practical use, such as storage in hospitals, than any formulation II-V.

Claims (3)

PATENT CLAIMS CLAIMS 1. A process for the preparation of a pharmaceutical composition comprising cyclosporin and a carrier comprising: 2 parts by weight of a natural oil is mixed with 1 part by weight of a transesterification product of 200-800 molecular weight polyethylene glycol, ethanol and a vegetable oil and 0.2 to 10 parts by weight of cyclosporin are used for 10 parts by weight of the transesterification product. (Priority: 5 March 5, 1979) 2. The process of claim 1 wherein the cyclosporin is cyclosporin A and / or dihydrocyclosporin C and / or isocyclosporin D. (Priority: March 5, 1979) 3. The process of claim 1 wherein the cyclosporin is cyclosporin A. (Priority: March 7, 1978)