Gelatin capsules with solid floor, including pharmaceutical compositions, containing no oils

 

(57) Abstract:

The pharmaceutical composition comprises as an active ingredient ciclosporin a surfactant and a hydrophilic phase. Surfactant has a value hydrophilic-lipophilic balance of at least 10 and is a reaction product of natural or hydrogenating vegetable oils and ethylene glycol. The hydrophilic phase contains a polyethylene glycol and at least one lower alkanol. Alkanol represents ethanol or propylene glycol. Each of these lower alkanols is present in amounts of less than 12% relative to the total weight of the composition. The composition is adapted for filling gelatin capsules with a hard surface. Compositions with cyclosporine have a small size, are stable when stored in the capsules, which increases the convenience of using them for patients. Capsules not become brittle. 16 C.p. f-crystals.

The invention relates to new pharmaceutical compositions containing as active ingredient cyclosporin a, also known as cyclosporine (hereinafter in the present description called cyclosporine).

Up to the present Vrelo use for the treatment of people. So, in the United States are only allowed SANDIMMUNE and NEORAL (cyclosporine for microemulsions).

These compositions can be applied in the form of a solution for a drink or in the form of gelatin capsules, soft coated. Such gelatin capsules, soft coated require special manufacturing techniques.

The compositions of the present invention are containing cyclosporine compositions that satisfy the requirements for regulatory approvals in the United States or in other countries, and can be produced in a form that can be entered in the form of gelatin capsules with a hard surface. Such capsules are well known in this area and can be manufactured and filled in the conventional manner.

One of the objects of the present invention is a pharmaceutical composition for oral administration containing cyclosporine a in mixture (I) surface-active substance with a value hydrophilic-lipophilic balance (products HLB) of at least 10, and optionally (II) increasing the viscosity of the agent and/or (III) a hydrophilic phase and the hydrophilic phase is a polyethylene glycol and/or (ness.)alkanol, provided that any (NISS. )alkanol is present in the amount of m is s for filling gelatin capsules with a solid surface and serves as its filler and practically does not contain any additional oil.

The proposed composition based on the use of a very small number of components, for example surfactants (including related by-products, usually formed during its manufacture, does not necessarily increase the viscosity agent (thickening agent) and, if necessary, additional hydrophilic phase (in addition to that which is present in the surface-active substance) selected from polyethylene glycol and/or (NISS. )alkanol, and (ness.)alkanol is present in amounts of less than 12%, for example 8%, relative to the weight of the composition.

A disadvantage of previously proposed compositions on the basis of cyclosporine is that they were not stable in gelatin capsules with a hard coating, for example, within 2-3 years, and had a bioavailability or variability, similar to those SANDIMMUNE and NEORAL. The compositions of the present invention have a very high stability. Capsules not become brittle.

Preferably the composition contains a small amount of other excipients. This gives the advantage of reducing the volume. Thus, preferably there is less than 5%, preferably less than 2% or 1% of the lipophilic fragm is for example alkanols, such as ethanol or propylene glycol.

The composition can contain polyethylene glycol. He can be a part of the surface-active substances, for example, if it is made by polyethoxysiloxane, or it can be added separately. The amount of this component may be, for example, from 1 to 40% of the composition. Preferably the polyethylene glycol having a molecular weight of, for example, from 200 to 600 daltons, is in a liquid state at 37oC.

Cyclosporine may be present in a standard preparation on the basis of cyclosporine dosage form, for example in quantities of 25, 50 or 100 mg per dosage form. Dosage form is a gelatin capsule with a hard coating, known in this field.

In the present invention proposed new glenavy based drugs cyclosporine, which satisfy the necessary requirements or significantly reduce known in the field of the difficulties associated with the use of cyclosporine therapy. In particular, it was found that the composition according to the invention is suitable for the manufacture of solid, semi-solid and liquid compositions containing cyclosporine in concentric the bedroom efficiency, for example, in relation to the characteristics of biological availability.

In particular, it was found that the compositions of the present invention allow effective dosage of cyclosporine along with increasing levels of absorption/bioavailability, and reduced variability of levels of absorption/bioavailability in relation to each individual patient treated with cyclosporine, and in relation to different individuals. When implementing the present invention can be obtained dosage forms based on cyclosporine, allowing the use of different doses to achieve a smaller variability of the obtained levels of cyclosporine in the blood/serum of individual patients, as well as between individuals in the group. Thus, the invention allows to reduce the levels of doses of cyclosporine needed for effective therapy. In addition, it allows for a more accurate standardization and optimization of the conditions of daily use doses of individual patients treated with cyclosporine, as well as for groups of patients undergoing the same treatment.

When more accurate standardiso, as well as doses and parameters of the reaction of the organism in patients in the group, the monitoring requirements may be reduced, which significantly reduces the cost of treatment.

By reducing the required dosage and standardization achieved characteristics bioavailability of the present invention also reduces the possibility of unwanted side effects, in particular nephrotoxic reactions in patients treated with cyclosporine.

The compositions of the present invention have a small size, are stable, which increases the convenience of using them for patients.

Surfactant preferably represents such authorized for use by the FDA (office for quality control of food, drugs and cosmetics), such as surfactant type GRAS. Examples of such surfactants are listed below.

1.1. Polyethoxysiloxane castor oil, for example, the interaction products of natural or hydrogenated vegetable oils and ethylene glycol, namely, polyethoxysiloxane natural or hydrogenated vegetable Maut to be obtained in a known manner, for example, by interaction of a natural or hydrogenated castor oil or its fractions with ethylene oxide, for example, in a molar ratio of from about 1:35 to about 1:60, with optional removal of free product polietilenglikolya components, for example according to the methods described in DE-OS 1182388 and 1518819. Particularly suitable are various surfactants, marketed under the trade name Cremophor. Most suitable are the products Cremophor RH40, having a saponification number of approximately 50-60, acid number <1, iodine value <1, a water content (Fischer) <2%, nD60approximately 1,453-1,457 and products HLB of approximately 14-16; Cremophor RH60, having a saponification number of approximately 40-50, acid number <1, iodine value <1, a water content (Fischer) about 4.5 to 5.5%, nD25approximately 1,453-1,457 and products HLB of approximately 15-17; and Cremophor EL, having a molecular weight (method steam osmometry) about 1630, a saponification number of approximately 65-70, an acid number of about 2, an iodine number of approximately 28-32 and nD25approximately 1,471 (cf. Fiedler in the mentioned place (loco citato), pp. 326-327). As such substances are also suitable DL for example, Nikkol HCO-60. Product Nikkol HCO-60 is a product of the interaction of hydrogenated castor oil and ethylene oxide, having the following characteristics: acid number of approximately 0.3, the number of saponification of approximately 47,4, a hydroxyl number of approximately 42,5, pH (5%) approximately 4,6, color ARNA approximately 40, tPLapproximately 36,0oC, the freezing point of approximately 32,4oWith water content (%, KF) approximately 0.03.

Such products contain hydrophilic part consisting of approximately 70-90% polyethoxylated esters of fatty acids and glycerol, as well as polyethoxylated fatty acids, and a hydrophilic portion of polyethylene glycol and ethoxylated glycerine (see, for example, Karl Muller, Tenside, year 3, 2nd edition, pages 37-45).

Preferred surface-active substance is polyethoxysiloxane hydrogenated castor oil Cremophor RH.

1.2. Esters of fatty acids and polyoxyethylenesorbitan (Polysorbate), for example, obtained by copolymerization of ethylene oxide with fatty acid esters and sorbitol and its anhydrides, for example, mono - and trilaurylamine, palmitinovaja, stearic and olejowego esters, for example of the type known and received in PR/BR> 20 [polyoxyethylene(20)sorbitanoleat],

40 [polyoxyethylene(20)servicemanagement],

60 [polyoxyethylene(20)servicemonitor],

80 [polyoxyethylene(20)servicemanual],

65 [polyoxyethylene(20)corbettreport],

85 [polyoxyethylene(20)sarbatorile],

21 [polyoxyethylene(4)sorbitanoleat],

61 [polyoxyethylene(4)servicemonitor]

81 [polyoxyethylene(5)servicemanual].

Especially preferred products of this class for use in the compositions according to the invention are the above products tween 40 and tween 80.

1.3. Polyethoxysiloxane fatty acids, for example, produced by the interaction of fatty acids with ethylene oxide, such as polyoxyl(40)stearate, for example polyethoxysiloxane stearic acid is marketed under the trade name Myrj (cf. Fiedler in the mentioned location, page 834), and also known Polyethoxysiloxane fatty acid, marketed under the trade names Cetiol HE (cf. Fiedler in the mentioned location, page 284); especially preferred product of this class for use in the compositions according to the invention is the product Myrj 52 having D25approximately 1,1, tPL

1.4. Polyethoxysiloxane monetary fatty acids and of glycerol, for example the esters of laurinovoj, stearic, aeroway or ezoterikovou acids, for example esters, marketed under the name Tagat O or L.

1.5. Polyoxyethylene monetary saturated WITH10-C22fatty acids, for example, substituted, for example, replacement WITH18fatty acids; for example, polietilenglikolya (PEG) ester 12-hydroxyoctadecadienoic acid, for example, where the PEG has a molecular weight of, for example, approximately 600-900, for example 660 Yes, for example, SOLUTOL H515, supplied by BASF, Ludwigshafen, Germany.

1.6. Copolymers of polyoxyethylene and polyoxypropylene, poloxamer, for example, known types, marketed under the trade names Pluronic and Emkalix (cf. Fiedler in the above-mentioned place, pages 956-958). Especially preferred product of this class for use in the compositions according to the invention is the product Pluronic F68 (poloxamer 188).

1.7. Propylene glycol mono - and diesters of fatty acids, such as propilenglikolstearat, propilenglikolstearat, propilenglikolstearat, propilenglikolstearat, propilenglikolstearat, propilenglikolstearat, propilenglikolem fluids Caprylic and capric acids, known and marketed under the trade name Migliol 840 (cf. Fiedler in the mentioned location, page 809). Migliol 840 has the following fatty acids:6a maximum of approximately 3%, C8approximately 65-80%, WITH10approximately 15-30%, WITH12a maximum of 3%. The acid number is at most 0.1, the number of saponification of approximately 320-340, iodine number is a maximum of 1.

Below are examples of ionic surfactants:

2.1. Dioctylamine, dioctylsulfosuccinate, di[2-ethylhexyl] succinate or sodium lauryl sulfate.

2.2. Phospholipids, in particular lecithins (cf. Fiedler in the above-mentioned place, pages 731-733). Lecithins suitable for use in compositions according to the invention, include, in particular, soya bean lecithins.

2.3. Salts of bile acids, for example alkali metal salts, for example taurocholate sodium.

Examples of other lipophilic surface-active substances suitable for use as components of surface-active substances are, for example, the following.

2.1. The products of the transesterification of natural triglycerides of vegetable oils and polyalkylene polyols. Such products of interesterification known in the t products of interesterification of different nature (for example, dehydrogenation) vegetable oils such as corn oil, palm kernel oil, almond oil, peanut oil, olive oil and palm oil and mixtures thereof with glycols, in particular polyethylene glycols having an average molecular weight of from 200 to 800. Preferred products are obtained by transesterification of 2 molar parts of a natural triglyceride vegetable oil with one molar part of polyethylene glycol (for example, having an average molecular weight of from 200 to 800). Various forms of the products of interesterification of this type are known and are sold under the trade name Labrafil [Ms. Fiedler in the mentioned location, page 707]. Especially preferred for use as components of compositions according to the invention are the following products: Labrafil M 1944 CS, the product of transesterification of palm kernel oil and polyethylene glycol, having an acid number of about 2, a saponification number of approximately 145-175 and iodine number of approximately 60-90; Labrafil M 2130 CS, the product of the interesterification WITH12-C18glycerides and polyethylene glycol, with tPLapproximately 35-40oC, acid number <2, a saponification number of approximately 185-200 and iodine value <3.oWith, and has an acid number of at most 2, the iodine number of at most 1, a saponification number of approximately 235-275, the percentage of monoglycerides approximately 40-50%, the percentage of free glycerol max 2%, tPLapproximately 24-26oWith the content of unsaponifiable products to a maximum of 0.3%, peroxide number max 1.

2.3. Esters of fatty acids and sorbitan, for example well-known products marketed under the trade name span, for example, including sorbitanoleat-monopalmitate, -monostearate, the fatty acids and ethers of pentaerythritol and polyalkyleneglycol, for example pentaerythritol-distearate-monolaurate, -monostearate and simple ester of pentaerythritol and polyglycol, and also esters of pentaerythritol and fatty acids (see Fiedler in the above-mentioned place, pages 923-924).

2.5. Monoglycerides, such as monooleate glycerin, monopalmitate glycerol and glycerol monostearate, for example well-known products marketed under the trade names Myvatex, Myvaplex and Myverol (cf. Fiedler in the mentioned location, page 836), and acetylated, for example mono-and diacetylpyridine monoglycerides, for example well-known products marketed under the trade name Myvacet (cf. Fiedler in the mentioned location, page 835).

2.6. Triacetate or (1,2,3)-glycerol triacetin (cf. Piedler in the mentioned location, page 952).

2.7. Sterols and their derivatives, such as cholesterol and derivatives thereof, in particular phytosterols, for example products, including sitosterol, campesterol or stigmasterol, and their adducts with ethylene oxide, for example soy sterols and their derivatives such as the products known under the trade name Generol (cf. Fiedler in the above-mentioned place, pages 554 and 555), in particular products Generol 122, 122 E5, 122 E10 and 122 E25.

It should be noted that the surfactant can be a complex smsmse, obtained, for example, by polyoxyethylene may contain other by-product, such as polyethylene glycol.

The composition of the invention may also contain a thickening agent (also called an agent that increases the viscosity).

Suitable thickeners can be known and used in this area substances, for example pharmaceutically acceptable polymeric materials and inorganic thickeners, which contribute to the rapid filling compositions and prevent leakage, such as thixotropic agents. They should also have the ability to rapidly dissolve (e.g., within 5 min) in gastric juices or water, or when the pH 1-2. An example of such thickeners are listed below.

3.1. Water-soluble polyethoxysiloxane esters of tocopherol and succinic acid (TPGA), for example, with the number of polymerization of about 1000, for example, supplied by the company Eastman Fine Chemicals, Kingsport, Texas, USA.

3.2. Water-soluble cellulose and cellulose derivatives, including alkylaryl, for example methyl-, ethyl - and propylethylene; hydroxyalkyl-cellulose, for example, hydroxypropylcellulose and hydroxypropylmethylcellulose, such as hydroxypropylmethylcellulose; and alati hydroxypropylmethylcellulose; salts of these compounds, such as sodium salt of carboxymethyl cellulose. Examples of such products are suitable for use according to the present invention are known products marketed under the trade names Klucel and Methocel (cf. Fiedler in the mentioned location, page 688 and 790).

3.3. Water-soluble polyvinylpyrrolidone, including, for example, poly-N-vinylpyrrolidone and vinylpyrrolidone copolymers, such as copolymers of vinylpyrrolidone and vinyl acetate, especially with low molecular weight. Examples of such compounds suitable for use according to the present invention are known products, marketed, e.g. under the trade name Kollidon (or Povidon in USA) (cf. Fiedler in the mentioned location, page 694 and 696), in particular products Kollidon 30 and 90.

3.4. Inorganic thickeners in small quantities, such as attapulgite, bentonite and silicates, including hydrophilic products on the basis of silicon dioxide, for example, alkylated (e.g., methylated) silica gels, in particular well-known products on the basis of colloidal silicon dioxide, marketed under the trade name Aerosil [see Handbook of Pharmaceutical Excipients, in the above-mentioned place, page 253 and 256], icii may also include one or more of the other ingredients, for example, in amounts of from 0.1 to 5%, in particular antioxidants [e.g., ascorbyl palmitate, butylhydroxyanisole (BHA) that is equivalent (OSH) and Tocopherols, for example-tocopherol (vitamin E)], corrigentov etc., Particularly preferably the use of an antioxidant, in particular tocopherol.

The ratio of ingredients in the compositions according to the invention, obviously, varies considerably depending on the specific type of the considered composition. Tech ratio in any particular case, as a rule, can be determined by a person skilled in the art. Therefore, it should be noted that all of the following nominal ratios and ranges of relative masses characterize only the preferred or specific embodiments of the invention and do not limit the scope of the invention.

a) Cyclosporine is usually present in an amount of 5 to 30 wt.%, preferably from about 10 to about 25 wt.% in terms of the total weight of the composition excluding the weight of the gelatin capsule with a hard surface.

b) If it consists of any glycol, it is typically present in amount from about 15 wt.% to about 30 wt.% Is any additional excipient, other than surfactants and used as a thickening agent, preferably present in amounts of from about 0.1 to 5 wt.% in terms of the total weight of the composition excluding the weight of the gelatin capsule with a hard surface.

In the composition described above compositions can additionally include a thickener, although, as mentioned earlier, this is generally less preferred. The number present thickener may vary, for example depending on the desired consistency of the final product, for example, depending on whether it is located in a thickened fluid form, for example, for filling capsules. The number, as it is obvious, must also depend on the nature of the selected thickener. In General, components (4) of the thickener, if present, are present in amount of about 25 wt.% in terms of the total weight of the composition, more preferably about 15 or 20 wt.%, for example, in amounts of from 0.5 or 5 to 15 or 20 wt.% in terms of the total weight of the composition.

The composition can also include additional additives or ingredients, such as described above. In particular, they may include antioxidants, naprimer, for example, in the amount of approximately 2.5 or 5 wt.% in terms of the total weight of the composition.

In the preferred embodiment, other excipients are missing. Therefore, the volume can be kept small, and the composition can be filled in capsules of size 1, 2 or 3.

It was found that the compositions have particularly preferable characteristics with the introduction oral route, for example, as regards consistency, and achieved a high level of bio-availability, as demonstrated in standard tests on people or, for example, on a hound dog. In particular, it was found that unlike other herbal systems, such as known in this field, such compositions are compatible with surface-active substances, such as salts of bile acids present in the gastrointestinal tract. In other words, they are completely dispersed in aqueous systems containing such natural surfactants and are therefore able to form a microemulsion system in situ, which are stable and in which there is no deposition or other violation of thin-specific patterns. Functional ability such sistemului salts of bile acids at any particular time or for any specific individual. Therefore, such compositions are particularly preferred according to the invention. Characteristics of bioavailability can be assessed in standard clinical experiments or on dogs using standard radioimmunoassay analysis for the presence of cyclosporine. In a preferred embodiment, the capsules have a short Tmax. Preferably after dilution with water the composition formed micellar solutions, in which it is possible to detect droplets, for example, a diameter of 10 to 150 nm.

The above composition should preferably be enclosed in a shell gelatin capsules with a hard surface, serving as a standard dosage forms intended for oral administration. If the compositions are in the form of standard dosage forms, each standard dosage form preferably contains from about 5 or 10 to about 200 mg of cyclosporine, more preferably from about 15 or 25 to about 150 mg, e.g. 25, 50 or 100 mg of cyclosporine. So, the standard dosage forms according to the invention is suitable for implementation on 1, 2 or 3 times a day and up to 5 times a day (for example, depending on the particular purpose of therapy, the phase of therapy is about 100 mg of cyclosporine per standard dosage form.

Additional details of the excipients listed in Fiedler.

Below the invention is illustrated in the examples, not limiting its scope.

Example 1

Gelatin capsules with a hard coating

Cyclosporine And 100 mg

Surfactant (Cremophor RH or twin) - 300 mg

Example 2

The composition has the same composition as in example 1, but additionally contains 10 mg TPGA.

Each composition has a biological profile for accessibility for people and dogs, for example with respect to AUC, Tmaxand Cmaxsimilar to the profile NEORAL.

Gelatin capsules paved remain stable for at least 2 years and still offers very good performance.

Example 3

Gelatin capsules with a hard coating

Cyclosporine And 50 mg

Surfactant (Cremophor RH or twin) - 300 mg

1,2-propylene glycol or ethanol - 8 wt.% in terms of the total weight of the entire composition

Example 4

Gelatin capsules with a hard coating

Cyclosporine And 50 mg

Surfactant (Cremophor RH or twin) - 300 mg

PEG 300 - 30 wt.% in terms of the total weight of all composition

1. W is in A, surfactant having a value of hydrophilic-lipophilic balance (products HLB) of at least 10 containing the reaction product of a natural or hydrogenating vegetable oils and ethylene glycol, and a hydrophilic phase containing a polyethylene glycol and at least one (NISS. ) alkanol selected from ethanol and propylene glycol, where each of the lower alkanols is present in amounts of less than 12%, calculated on the total weight of the composition excluding the weight of the gelatin capsule with a hard surface.

2. Gelatin capsule with a solid floor under item 1, where the surfactant additionally comprises a fatty acid ester and polyoxyethylenesorbitan.

3. Gelatin capsule with a solid floor under item 2, where the surfactant additionally comprises a fatty acid ester and sorbitan.

4. Gelatin capsule with a hard coating according to any one of paragraphs. 1-3, where the lowest alkanol is ethanol.

5. Gelatin capsule with a hard coating according to any one of paragraphs. 1-3, where the lowest alkanol is propylene glycol.

6. Gelatin capsule with a hard coating according to any one of paragraphs. 1-3, where the lowest alkanol is ethanol and propylene glycol.

7. is in an amount of 5 to 30 wt. % based on the total weight of the composition excluding the weight of the gelatin capsule with a hard surface.

8. Gelatin capsule with a hard coating according to any one of the preceding paragraphs, where the polyethylene glycol is in a liquid state when heated to 37oC.

9. Gelatin capsule with a hard coating according to any one of the preceding paragraphs, where the polyethylene glycol has a molecular weight of from 200 to 600 daltons.

10. Gelatin capsule with a hard coating according to any one of the preceding paragraphs, where the polyethylene glycol is present in an amount of from 1 to 40% based on the total weight of the composition excluding the weight of the gelatin capsule with a hard surface.

11. Gelatin capsule with a solid floor under item 8 or 9, where the pharmaceutical composition is semi-solid and cyclosporine dissolved in it.

12. Gelatin capsule with a solid floor under item 8 or 9, where the pharmaceutical composition is a liquid and cyclosporine dissolved in it.

13. Gelatin capsule with a hard coating according to any one of the preceding paragraphs, where the pharmaceutical composition when diluted with water, forms a micellar solutions.

14. Gelatin capsule with a solid floor under item 13, the smoke coating according to any one of the preceding paragraphs, where everyone (NISS. )alkanols is present in an amount of from 8 to less than 10% based on the total weight of the composition excluding the weight of the gelatin capsule with a hard surface.

16. Gelatin capsule with a hard coating according to any one of the preceding paragraphs, comprising less than 5% of the lipophilic component in contrast to the one that is present in the surface-active substance.

17. Gelatin capsule with a hard coating according to any one of the preceding paragraphs, are able to form a microemulsion systems in situ.

Priority points:

30.01.1997 - PP. 1-17;

07.02.1997 - PP. 1-17 (clarification of their signs).

 

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