JP2006001947A - New cyclosporine medicine - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a new medicine containing cyclosporine as an active ingredient. <P>SOLUTION: A medicinal composition comprises (a) cyclosporine as the active ingredient, (b) a fatty acid saccharide mono ester, and (c) a diluent or a carrier. <P>COPYRIGHT: (C)2006,JPO&NCIPI

Description

Detailed Description of the Invention

  The present invention relates to a novel preparation containing cyclosporine as an active ingredient.

  Cyclosporins include a group of structurally unique cyclic poly-N-methylated endecapeptides that usually have pharmacological, in particular immunosuppressive, anti-inflammatory and / or antiparasitic activity. The first isolated cyclosporine was the natural fungal metabolite “Cyclosporin” (Ciclosporin or Cyclosporine), also known as Cyclosporin A, which is marketed under the trade name SandyMun (SANDIMMUN or SANDIMMUNE). . “Cyclosporine” is a cyclosporin represented by the formula (A).

[式中、−ＭeＢmt−は、式(Ｂ)

(式中、−x−y−は−ＣＨ＝ＣＨ−(トランス)である)
で示されるＮ−メチル−(４Ｒ)−４−ブタ−２Ｅ−エン−１−イル−４−メチル−(Ｌ)トレオニル残基を表す]

[Where -MeBmt- is the formula (B)

(Wherein -x-y- is -CH = CH- (trans))
Represents an N-methyl- (4R) -4-but-2E-en-1-yl-4-methyl- (L) threonyl residue represented by

  As this type of matrix, “cyclosporine” has received the most attention. The main area of clinical research on “cyclosporine” is as an immunosuppressant, especially for organ transplants such as heart, lung, cardiopulmonary, liver, kidney, pancreas, bone marrow, skin and corneal transplants and especially for recipients of atypical organ transplants. It was about application. “Cyclosporine” has gained significant achievements and reputation in this field.

  At the same time, the applicability of `` cyclosporine '' to various autoimmune diseases and inflammatory conditions, especially inflammatory conditions due to etiology including autoimmune elements such as arthritis (e.g. rheumatoid arthritis, chronic progressive arthritis and osteoarthritis) and rheumatic diseases, Very strong, reports and results in in vitro, animal models and clinical trials are widely described in the literature. Specific autoimmune diseases for which "cyclosporine" therapy has been proposed or applied include autoimmune blood diseases (e.g., hemolytic anemia, non-renewable anemia, congenital dysplastic anemia, and idiopathic thrombocytopenia) Systemic lupus erythematosus, polychondritis, scleroderma, Wegener's granulomatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, psoriasis, Steven-Johnson syndrome, idiopathic sprue, autoimmune inflammatory bowel disease ( Including ulcerative colitis and Crohn's disease), endocrine eye disease, Graves' disease, sarcoidosis, multiple sclerosis, primary biliary cirrhosis, juvenile diabetes (type 1 diabetes mellitus type I), uveitis (anterior) And posterior), dry keratoconjunctivitis and spring keratoconjunctivitis, interstitial pulmonary fibrosis, psoriatic arthritis and glomerulonephritis (eg, idiopathic nephrotic syndrome or fine With or without nephrotic syndrome, including lesional nephropathy).

  Another area of research is the potential applicability as anti-parasites, especially antigenic animal agents, possible applications including the treatment of malaria, coccidioidomycosis and schistosomiasis, and more recently other anti-neoplasms, for example Or the use in the treatment of cancer as an agent which cancels or eliminates the resistance to cytostatic therapy is suggested.

Since the first discovery of cyclosporine, a wide range of natural cyclosporines has been isolated and identified, and many additional non-natural cyclosporines have been produced by application of total or semi-synthetic means or modified culture techniques. That is, there are a wide variety of types encompassed by cyclosporines, for example, natural cyclosporin A to Z [reference, traversal, etc. 1, “Helv. Chim. Acta.” 60 , 1247-1255 (1977). , Traversal, etc., 2, “Helv. Chim. Acta.” 65 , number 162, 1655-1667 (1982), Kobel et al., “European Journal of Applied Microbiology and Biotechnology "(Europ. J. Applied Microbiology and Biotechnology) 14 , 273-240 (1982), and von Baltberg et al.," Progress in Allergy ", 38 , 28-45 (1986). )], And various non-natural cyclosporine derivatives and artificial or synthetic cyclosporines, eg Ebaiwayuru dihydro - cyclosporins [in this case, by saturating the -x-y- portion -MeBmt- residue (the formula B), -x-y - = - CH 2 -CH 2 - can be obtained] , Derivatized cyclosporines (eg, when another substituent is introduced into the α-carbon atom of the sarkosyl residue at position 3 of the cyclosporine molecule), cyclosporines where the -MeBmt-residue exists in an isomeric form (eg, -When the configuration between the 6 'and 7' positions of the MeBmt-residue is cis rather than trans), and the use of a fully synthetic cyclosporine production method developed by Wenger, for example, Cyclosporines incorporated at specific locations [e.g., traverser 1, traverser 2 and corbel, supra, U.S. Pat. Nos. 4,810,985, 4,210,581 and (. Transp.Proc) No. 4,220,641, European Patent Publication No. 0034567, same No. and the No. 0,296,122 0,056,782, International Patent Publication No. WO86 / 02080, Wenger 1, "trans plantation Proceedings" 15, Appendix 1: 2230 (1983), Wenger 2, “Angevante Hemmy International Edition in English” (Angew. Chem. Int. Ed.), 24 , 77 (1985) and Wenger 3, “Progress in the Chemistry”. Of organic chemistry products (see Progress in the Chemistry of Organic Natural Products), 50 , 123 (1986)].

That is, as a kind contained in cyclosporine, for example, [Thr] ²⁻ , [Val] ² −, [Nva] ² − and [Nva] ² − [Nva] ⁵ − “cyclosporin” (respectively cyclosporin C, D , G and M), [3′-O-acyl-MeBmt] ^1- “cyclosporine” (also known as cyclosporin A acetate), dihydro- [MeBmt] ^1- [Val] ² - "cyclosporin" (dihydro - also known as cyclosporin D), 3'-desoxy-3'-oxo - ^{[MeBmt] 1} - ^{[Val] 2} - and - ^{[Nva] 2} - "cyclosporin", [ (D) ^{fluoromethyl-Sar] 3} - ^{"cyclosporin", [(D) Ser] 8} - as "cyclosporine" (cyclosporine H - "cyclosporin", ^{[MeIle] 11} - "cyclosporin", [(D) ^{MeVal] 11} Also known ), [MeAla] ⁶ - ^{"cyclosporine", [(D) Pro] 3} - there is a such as "cyclosporine".

[These are defined according to the current customary nomenclature for cyclosporines, with reference to the structure of “cyclosporine” (ie, cyclosporin A). This indicates an amino acid residue that is different (present) from the amino acid residue present in “cyclosporin” (eg, “[(D) Pro] ³ ” indicates that the cyclosporin in question is in position 3 -Indicates having-(D) Pro-, not residues), and then applying the term "cyclosporin" to characterize the remaining residues that match the residues present in "cyclosporin" Done. Individual residues are numbered starting from the 1-position residue -MeBmt-, -dihydro-MeBmt- or its equivalent residue. ]

  In addition, a great many of these cyclosporines exhibit pharmacological usefulness comparable to “cyclosporine” or more specific utility, such as activity that counteracts tumor resistance to cytostatic therapy, especially as their therapeutic agents. Many proposals concerning applicability are described in the literature.

  “Cyclosporine” has made a significant contribution to the treatment of organ transplant areas and autoimmune diseases in particular, but the difficulties encountered when providing a more effective and convenient means of administration, and undesirable side effects, particularly the nephrotoxic response The occurrence of this is a clear and serious obstacle to its widespread use or application. Cyclosporines are characterized by high hydrophobicity. For example, liquid formulations proposed for oral administration of cyclosporines have traditionally been based primarily on the use of ethanol and oils or similar excipients as carrier media. That is, the commercially available “cyclosporine” drinking liquid uses Labrafil® as a surfactant and ethanol and olive oil as a carrier medium (see, for example, US Pat. No. 4,388,307). However, the use of drinking fluids and similar compositions that have been proposed in the art is associated with various difficulties.

  First, because of the need to use oils or oil-based carriers, an unpleasant taste can be added to the formulation, otherwise the mouthfeel can deteriorate, especially for long-term therapeutic purposes. These effects can be masked by formulating into gelatin capsule form. However, to maintain cyclosporine in solution, the ethanol content must be kept high. For example, when opened, cyclosporine precipitates appear as a result of evaporating ethanol from, for example, capsules or other forms. When formulating these compositions, for example in the form of gelatin soft capsules, this particular problem necessitates packaging of the product enclosed in a hermetic compartment, such as a hermetic blister or an aluminum foil blister-package. As a result, the product is bulky and expensive to manufacture. The storage characteristics of the formulation are far from ideal.

  Also, the level of bioavailability achieved using existing oral cyclosporine dose systems is low and exhibits a wide range of variation between individuals, individual patient types, and even in the case of a single individual at different points in the course of treatment. That is, reports in the literature show that the average absolute bioavailability provided by currently available therapies using commercially available “cyclosporine” drinking fluid is only about 30%, and between individual groups, such as the liver ( Remarkably variable among transplant recipients (relatively low bioavailability) and bone marrow (relatively high bioavailability). It has been reported that the range of variation in bioavailability between subjects can be as high as 1 or a few percent or as high as 90% or more depending on the patient. And as already mentioned, significant time course changes in the bioavailability of individuals are frequently observed.

  In order to achieve effective immunosuppressive therapy, cyclosporine blood or serum levels must be maintained within a certain range. In this case, the required range is the specific condition being treated, for example whether the treatment is aimed at preventing transplant rejection or controlling autoimmune diseases, and another immunosuppressive therapy is cyclosporine. It can change depending on whether or not it is used simultaneously with therapy. The level of bioavailability achieved by conventional dosage forms varies widely, so the daily dose required to achieve the required serum levels will also vary considerably between individuals and even in single individuals To do. For this reason, it is necessary to monitor blood / serum levels in patients receiving cyclosporine therapy at regular and frequent intervals. Blood / serum level monitoring, generally performed using RIA or equivalent immunoassay techniques, such as monoclonal antibody-based technology, must be done in a regular manner. This inevitably is time consuming and inconvenient and substantially increases the total cost of treatment.

  Above all, these very obvious practical obstacles lie in the occurrence of the undesirable side effects already mentioned above, which are observed when using available oral dosage forms.

  Various proposals have been suggested in the art to overcome these problems, including both solid and liquid oral dosage forms. Specifically, Japanese Patent Application No. 60-71682 (Japanese Patent Application Laid-Open No. 61-280435) by Takada et al. Is a means of increasing lymphatic gland delivery of cyclosporine by specifically administering it in combination with a surfactant. Indicates application. A general list of surfactants that can be used includes sucrose (sucrose) fatty acid esters such as sucrose oleate, palmitate or stearate, and other fatty acid esters, particularly sorbitan fatty acid esters such as sorbitan oleate, palmitate Or stearate is included. Although the use of both mono- and poly-esters has been shown, mono- or di-esters are generally suggested as preferred. Other surfactants listed include known products marketed under the trade names of polyoxyethylated hydrogenated vegetable oils, such as Cremophor RH and Nikkor HCO 60, which are clearly described, for example, by the saccharose ester interface described above. It has been shown to be preferred over the active agent.

Example 3 of the Japanese application describes a method for obtaining an aqueous preparation containing a saccharose fatty acid ester identified as F160 as a surfactant component. This formulation contains 3.5 mg “cyclosporine” and 2 mg saccharose ester in 1 ml H ₂ O. To achieve dispersion of “cyclosporine”, sonication at 100 W for 5 minutes is required. The resulting formulation, described as “clear solution”, is used directly in animal models to investigate relative lymph gland absorption. If the solubility of “cyclosporine” in H ₂ O is very low and a small amount of surfactant is used, it is clear that the claimed solution is an artifact of the sonication process. The achieved “cyclosporin” concentration is, for example, inappropriately low for oral dosage forms and because this formulation is inherently unstable, it is virtually excluded as a practical or commercial formulation of any kind Yes. It is essentially an experimental system that allows laboratory research. There is no suggestion for the use of surfactants in any other part of the specification except for the part relating to lymph gland delivery.

  Similarly, Japanese Patent Application No. 62-193129 (Japanese Patent Laid-Open No. 1-038029) by Takada et al., For example, with sucrose, sorbitol, tartaric acid, urea, cellulose acetate phthalate, methacrylic acid / methyl, together with a small amount of surfactant. Disclosed is a powder formulation containing cyclosporine dispersed in a solid non-surfactant carrier phase comprising methacrylate or hydroxypropylmethylcellulose phthalate. In addition, a surfactant is added together with a target for enhancing lymphatic delivery, and in the meaning of this specification, this application is clearly a practice intended to apply the teachings of Japanese Patent Application No. 60-71682 mentioned above. It is aimed at providing effective means. Saccharose esters as possible surfactant components are omitted in this case. Of the list of possible surfactant components, sorbitan esters are reserved. However, Nikkor HCO 60 type products have also been shown to be preferred as surfactants, and Nikkor HCO 60 is the only surfactant used in the examples. The alleged improvement in lymph gland delivery has not been shown to provide any practical benefit or to overcome some of the aforementioned problems, for example in cyclosporine therapy that the industry has previously faced .

  The present invention provides a novel cyclosporine formulation comprising a fatty acid saccharide monoester as the main carrier component. These solve or substantially reduce the problems in cyclosporine, such as “cyclosporin” therapy, that the industry has faced so far. In particular, the composition of the present invention enables the production of solid, semi-solid and liquid compositions containing cyclosporine at a concentration sufficiently high to allow, for example, conventional oral administration, while at the same time providing, for example, bioavailability properties. It has been found that an improvement in efficacy is achieved.

  More particularly, the composition according to the invention increases the level of absorption / bioavailability at the same time and achieves absorption / biology achieved both in individual patients and on an individual basis receiving cyclosporine therapy. It has been found to enable effective cyclosporine administration that reduces variability in the level of availability. By applying the teachings of this invention, it is possible to obtain a cyclosporine dosage form that reduces the variability in cyclosporine blood / serum levels achieved between doses to individual patients and between individuals / individual patient groups. That is, the present invention allows for the reduction of cyclosporine dose levels required to achieve effective treatment. Furthermore, the present invention allows for more precise standardization and optimization of ongoing daily dose requirements for individual subjects receiving cyclosporine therapy and groups of patients undergoing equal treatment.

  By more accurately standardizing individual patient dose ratios and blood / serum level responses, as well as dose and response parameters for patient groups, monitoring requirements can be reduced, ie, treatment costs can be substantially reduced.

  By reducing the required cyclosporine dose / standardizing the bioavailability characteristics achieved, the invention also reduces the occurrence of undesirable side effects, particularly nephrotoxic responses, in patients undergoing cyclosporine therapy. Provide a means that can be.

  Furthermore, the present invention allows for the production of compositions that are non-alkanol-based, for example ethanol-free or substantially free. These compositions avoid the aforementioned stability and associated processing problems typical of known alkanolic compositions. That is, the present invention particularly eliminates or substantially eliminates packaging problems such as those described above, eg, with respect to formulation, eg, as a capsule, eg, gelatin hard or soft capsule form, and / or, eg, with respect to eg gelatin soft encapsulated form. The composition is provided with a reduction.

More specifically, the present invention
a) cyclosporine as active ingredient,
b) fatty acid saccharide monoesters and
c) includes a diluent or carrier,
(i) component (c) is a solvent for both components (a) and (b), and components (a) and (b) each independently have a solubility of at least 10% in component (c) at ambient temperature Have or
(ii) Component (c) is a solvent for both components (a) and (b), and components (a) and (c) are 1: 0.5-50 ppw [(a) :( c )], Or
(iii) component (c) is a solvent for both components (a) and (b) and the composition is formulated in a solid unit dosage form suitable for oral administration, or
(iv) component (c), poly has a viscosity at 50 ° C. of 15000mPa.s with average molecular weight or a number of 7000 at most -. _{(C 2} - ₄ alkylene) - or glycols, or C _{3 - 5} Contains an alkylene polyol ether or ester, or
(v) the composition is non-aqueous or substantially non-aqueous, or
(vi) component (c) comprises a solid polymer carrier, an organo-silicon oxide polymer or a paraffinum per-liquidum or a paraffinum sub-liquidum; (a) is present in the composition as a solid solution in (b),
A pharmaceutical composition is provided.

  The above-defined compositions are described in French Patent Application No. 8811953 and USSN 07/243777, DOS No. 38304945, Japanese Patent Application No. 63-231396 and British Application No. 8821443.9 (first in France). , Published March 17, 1989, No. 2,620,336), and new and particularly advantageous modifications of the subject matter claimed comprehensively in corresponding applications in other world countries.

  The above definitions (i) to (vi) should be understood as compatible with each other. That is, the composition of the present invention includes a composition defined according to any one or more of the defined restrictions (i) to (vi). That is, a preferred composition according to the present invention conforms to any two or more of (i) to (v), for example.

  The term “pharmaceutical composition” as used in this specification, including the claims, refers to the composition as defined in which the individual components or materials are themselves pharmaceutically acceptable, eg Where oral administration is anticipated, it should be understood as acceptable for oral use, or where topical administration is expected, acceptable as topical use.

A preferred cyclosporin as component (a) is “cyclosporine”. A further preferred component (a) is [Nva] ^2- “cyclosporine”, also known as cyclosporin G.

  The preferred component (b) used in the composition of the invention is a water-soluble fatty acid saccharide monoester, for example having a solubility of at least 3.3% in water at ambient temperature, ie 30 ml of water at ambient temperature. Fatty acid monoesters of saccharides that are soluble in water in an amount of at least 1 g of monoester per unit.

The fatty acid portion of component (b) can comprise saturated or unsaturated fatty acids or mixtures thereof. Particularly suitable component (b), C 6 _{- 18} fatty acid saccharide monoesters, in particular water soluble C _{6 -} is a ₁₈ fatty acid saccharide monoesters. Particularly suitable components (c) are caproic acid (C ₆ ), caprylic acid (C ₈ ), capric acid (C ₁₀ ), lauric acid (C ₁₂ ), myristic acid (C ₁₄ ), palmitic acid (C ₁₆ ). ), Oleic acid (C ₁₈ ), ricinoleic acid (C ₁₈ ) and 12-hydroxystearic acid (C ₁₈ ) saccharide monoesters, in particular lauric acid saccharide monoesters.

The saccharide moiety of component (b) may contain a suitable sugar residue, such as a mono-, di- or tri-saccharide residue. Suitably the saccharide moiety comprises a di- or tri-saccharide residue. Preferred component (b), C 6 _- containing saccharide monoesters - ₁₄ fatty di - saccharide monoesters and C _{8 - 18} fatty acids birds.

  Particularly suitable saccharide moieties are saccharose and raffinose residues. That is, particularly suitable component (b) is saccharose monocaproate, saccharose monolaurate, saccharose monomyristate, saccharose monooleate, saccharose monoricinoleate, raffinose monocaproate, raffinose monolaurate, raffinose Monomyristate, raffinose monopalmitate and raffinose monooleate. The most preferred component (b) is raffinose monolaurate and especially saccharose monolaurate.

Component (b) preferably has a hydrophilic-lipophilic balance (HLB) of at least 10.
Component (b) suitably has an ester residue purity of at least 80%, more preferably at least 90%, most preferably at least 95%. Component (b) suitably has a melting point of from about 15 ° C to about 60 ° C, more preferably from about 25 ° C to about 50 ° C.

  According to the above definitions (ii) and (iii) applied to the composition of the invention, the defined component (c) is that both components (a) and (b) are at ambient temperature, for example about 20 ° C. It is a material that exhibits considerable solubility at temperature. Preferred component (c) is that (a) and (b) are independently at least 10% [required by definition (i)] at ambient temperature, preferably at least 25%, most preferably at least 50% (eg The component (a) or (b) independently has a solubility of at least 100 mg, preferably 250 mg, most preferably at least 500 mg / ml. Particularly preferred material conditions are when component (a) has a solubility of at least 10%, preferably at least 25%, most preferably 50% and / or component (b) is at least 100%, more preferably Has a solubility of at least 200%, most preferably at least 300% (eg when component (b) has a solubility of at least 1000, more preferably 2000, most preferably at least 3000 mg / ml).

Component (c) suitable for use in the composition of this invention is:
c ¹ ) ethanol,
c _{²⁾ C} ² _{- 4} alkylene glycols,
c _{³⁾ C} ³ _{- 5} alkylene - polyols,
c ⁴⁾ poly - (C _{2 - 4} alkylene) glycols and c ⁵⁾ C _{3 - 5} alkylene - containing polyol ethers also esters and mixtures thereof.

  However, according to the general purpose of this invention, the use of ethanol is generally less preferred, whether alone or mixed with any other component (c).

Component (c) C _{2 -} when containing ₄ alkylene glycol (c ^2), which is preferably propylene glycol, and most preferably 1,2-propylene glycol. When containing ₅ alkylene polyol (c ^3), which is preferably C _{3 - -} Component (c) is C ₃ a ₅ alkylene triol, most preferably glycerol.

Component (c) is poly - when containing _- (C _{2 4} alkylene) glycol (c ^4), which is preferably a polyethylene glycol. When used in the compositions of this invention, the components are preferably at most about 7000 [see definition (vi)], for example 6600 or less, more preferably at most about 2000, for example 1600 or less, most preferably at most. It has an average molecular weight of about 500. Preferably, the components have a viscosity of at most about 15000 mPa.s., more preferably at most about 1000 mPa.s., most preferably at most about 200 mPa.s. at 50 ° C. or more suitably at ambient temperature. [See definition (iv)]. Polyethylene glycols suitable for use as component (c) are described, for example, in Feeder, “Lexikon der Hilfstoffe”, Second Revised and Expanded Edition, (1981) Volume 2, pages 726-731. The ones described, in particular PEG products (polyethylene glycol) 200, 300, 400 and 600 and PEG 1000, 2000, 4000 or 6000, in particular 200, 300 and 400, for example substantially according to the following physical properties.

When containing ₅ alkylene polyol ethers or esters (c ^5), which is preferably C _{3 - -} Component (c) is C ₃ a ₅ alkylene triol, in particular glycerol, ethers or esters. Suitable components (c ^5), the mixed ethers or esters, i.e. components including other ether or ester materials, for example, C _{3 - 5} alkylene triol esters with other mono-, - di - or poly - ols and the Contains transesterification products.

Particularly suitable components (c ^5), the mixed C _{3 - 5} alkylene triol / poly - (C _{2 - 4} alkylene) glycol fatty acid esters, especially mixed glycerol / polyethylene - a glycol fatty acid esters - or polypropylene.

The component (c ⁵⁾ which are particularly suitable for use according to the invention, glycerides, e.g. triglycerides and poly - (C _{2 - 4} alkylene) glycols, such as poly - glycerol and Noto transesterification with ethylene glycol and optionally There is a product obtained by These transesterification products, generally, poly - (C _{2 - 4} alkylene) glycol poly, for example, glycerides in the presence of polyethylene glycol and, optionally, glycerol, obtained for example by alcoholysis of triglycerides (i.e., glycerides -Implementation of transesterification to alkylene glycol / glycerin component, ie by poly-alkylene glycolysis / glycerin degradation). In general, the reaction is carried out by reaction of the indicated components (glycerides, polyalkylene glycols and optionally glycerin) in an inert atmosphere at high temperatures with continuous stirring.

Preferred glycerides are natural and hardened oils, particularly vegetable oils, fatty acid triglycerides, for example _- is a (C _{10 22} fatty acid) triglycerides. Suitable vegetable oils, for example olive, almond, peanut, coconut, palm, soybean and wheat germ oils and, in particular _- is (C _{12 16} fatty acids), natural or hardened oils rich in ester residue.

  Preferred polyalkylene glycol materials are polyethylene glycols, particularly polyethylene glycols having a molecular weight of about 500 to about 4000, such as about 1000 to about 2000.

That Suitable components (c ^5), the small amounts of free C _{3 - 5} alkylene triol and free poly - with _- (C _{2 5} alkylene) glycol, C ₃ in the relative amounts may vary _{- 5} alkylene triol esters such as mono- - containing mixture consisting esters of -, di - and tri - esters and poly (C _{2 - 4} alkylene) glycol mono - and di. As mentioned earlier in this specification, the preferred alkylene triol moiety is glyceryl. Preferred polyalkylene glycol moieties, particularly polyethylene glycyl having a molecular weight of from about 500 to about 4000, and preferred fatty acid moieties _{are C 10 -} is a ₂₂ fatty acid ester residues _{- 22} fatty acid ester residue, in particular saturated _{C 10} .

Thus, in other words, particularly suitable components (c ⁵ ) are natural or hydrogenated vegetable oils and polyethylene glycols and optionally transesterification products of glycerin, or glyceryl mono-, di- and tri-C _{10- 22} fatty acid esters and polyethylene glycyl mono - and di -C 10 _{- 22} fatty acid esters composition of a (optionally e.g. minor amounts of free glycerol and free polyethylene glycol comprises obtaining together) or containing or these components Can be defined as

Preferred vegetable oils, polyethylene glycols or polyethylene glycol moieties and fatty acid moieties for the above definitions are as described above. Particularly suitable components (c ⁵ ) mentioned above for use in this invention are known products marketed under the trade name Gelucir, in particular i) gelsil 33/01, melting point = about 33-38 ° C. and
Saponification number = about 240/260,
ii) Gelsil 35/10, melting point = about 29-34 ° C and
Saponification number = about 120-140,
iii) Gelsil 37/02, melting point = about 34-40 ° C. and
Saponification number = about 200-220,
iv) Gelsil 42/12, melting point = about 41-46 ° C. and
Saponification number = about 95-115,
v) Gelsyl 44/14, melting point = about 42-46 ° C. and
Saponification number = about 75-95,
vi) Gelsil 46/07, melting point = about 47-52 ° C and
Saponification number = about 125-145,
vii) Gelsil 48/09, melting point = about 47-52 ° C. and
Saponification number = about 105-125,
viii) Gelsil 50/02, melting point = about 48-52 ° C. and
Saponification number = about 180-200,
ix) Gelsil 50/13, melting point = about 46-41 ° C and
Saponification number = about 65-85,
x) Gelsil 53/10, melting point = about 48-53 ° C. and
Saponification number = about 95-115,
xi) Gelsil 62/05, melting point = about 60-65 ° C. and
The saponification number is about 70-90.

The products (i) to (x) all have an acid value = <2. Product (xi) has an acid number = <5. The products (ii), (iii) and (vi) to (x) all have an iodine number = <3. Product (i) has an iodine number = ≦ 8. Products (iv) and (v) have an iodine number = <5. Product (xi) has an iodine number = <10. A component (c ⁵ ) having an iodine number = <1 is generally preferred. Obviously, mixtures of the above components (c ⁵ ) can also be used in the compositions of this invention.

When using the component (c) specially mentioned so far [that is, the component according to any of the above definitions (i) to (iv) or the component described in the items (c ¹ ) to (c ⁵ )] The composition generally comprises component (a) in a carrier medium comprising components (b) and (c). Typically, components (a) and (b) are each present in the form of a dispersion or solution of the composition of the invention, such as a molecular or micellar dispersion or solution (including solid solutions where appropriate). That is, component (a) is generally present in a dispersion or solution containing both components (b) and (c), and component (b) is present in a solution containing (c). Component (b) generally acts as a carrier or solubilizer (before and / or after administration) for component (a) in the compositions of this invention, and component (c) acts as a carrier or fluidizing agent. . (Of course, this invention should not be understood as being limited in any way to the specific functional relationship between components (a), (b) and (c) unless otherwise specified.)

  Furthermore, when using the aforementioned component (c), the composition of this invention is preferably formulated as a solid unit dosage form suitable for oral administration, for example a gelatin hard or soft capsule form suitable for oral administration. [See definition (iii)]. These unit dosage forms, which will be described in more detail later, preferably comprise, for example, 2 to 200 mg of component (a) per unit dose.

  When component (c) is used, components (a) and (c) are preferably added at a ratio of 1: 0.5 to 50 ppw [(a) :( c)] [see definition (ii)]. Present in the inventive composition. Components (a) and (b) are preferably present in a ratio of 1: 3 to 200 ppw [(a) :( b)].

  When using the aforementioned component (c), the composition of the invention is further non-aqueous or substantially non-aqueous [see definition (v)], for example having a water content based on the total weight of the composition, Preferably it is less than 20%, more preferably less than 10%, more preferably less than 5%, 2% or 1%.

From the foregoing, the present invention also provides, in a series of embodiments,
-Comprising the component (a), the component (b), and a diluent selected from any ^{one of the} components (c ¹ ) to (c ⁴ ) or a mixture thereof, of the above definitions (ii) to (v) A pharmaceutical composition according to any one of the above,
A pharmaceutical composition comprising said components (a), (b) and (c ² ) and according to said definition (ii), (iii) or (v), and-said components (a), (b) and (c A pharmaceutical composition comprising ⁵ ) is provided.

Component (c) [ie, the component according to any one of the definitions (i) to (iv) or the component according to any one of (c ¹ ) to (c ⁵ )] specifically mentioned above is contained in the composition of the present invention. Component (a) and (c) are preferably present in the composition in a ratio of about 1: 0.5 to 50 ppw. More preferably, components (a) and (c) are about 1: 1 to 10, more preferably 1: 1 to 5, most preferably about 1: 1.5 to 2.5, such as about 1: 1. .6 or 1: 2 ppw [(a) :( c)]. Components (a) and (b) are suitably present in the composition in a ratio of about 1: 3 to 200, preferably about 1: 3 to 100, more preferably about 1: 3 to 50 ppw. More preferably, components (a) and (b) are about 1: 5-20, preferably about 1: 5-10, most preferably about 1: 6.0-6.5, such as about 1: 6. .25 ppw [(a) :( b)].

  When the composition of this invention comprises sucrose monolaurate as component (b) and 1,2-propylene glycol as component (c), components (a) and (b) are preferably about 1: 6 to Present in a ratio [(a) :( b)] of 7 ppw and components (a) and (c) are preferably about 1: 1.5 to 2.5, for example about 1: 2 ppw [(a) :( c)].

  A composition according to the invention comprising said component (c) is for example for oral, parenteral or topical application, e.g. skin, for intra-lesional injection, e.g. in the treatment of the autoimmune condition of the eye, e.g. treatment of said condition or e.g. psoriasis Or it may be manufactured in a dosage form suitable for ophthalmic application, eg application to the surface of the eye.

Suitably, these compositions are made up in unit dosage form, whether orally or otherwise.
Of course, the amount of component (a) present in these unit dosage forms will vary depending upon, for example, the condition being treated, the intended mode of administration and the desired effect. In general, however, these unit dosage forms preferably contain from about 2 to about 200 mg of component (a), eg, “cyclosporine” per unit dose.

  Dosage forms suitable for oral administration include, for example, liquids, granules and the like. However, preference is given to solid unit dosage forms, such as tablets or encapsulated forms, in particular gelatin hard or soft capsule forms. Their oral unit dosage form is preferably about 5 to about 200 mg, more preferably about 10 or 20 to about 100 mg, for example 15, 20, 25, 50, 75 or 100 mg of component (a) per unit dose. For example, “cyclosporine”.

  Compositions according to this invention comprising said component (c) are those that exhibit modified release characteristics, e.g. delayed release of component (a) or prolonged release of component (a) after oral administration, for example. It has yet another advantage that it can provide a base for the composition. These compositions further comprise a component (d) that can modify the release characteristics of the composition with respect to component (a). These components (d) include, for example, polymeric excipients, in particular thickeners, such as polymeric or colloidal thickeners, as well as water-swellable agents, such as water-swellable polymers or colloids.

Suitable components (d) are known in the art and include the following:
d ¹ ) Polyacrylate and polyacrylate copolymer resins, such as polyacrylic acid and polyacrylic acid-methacrylic acid resins, such as the known products marketed under the trade name Carbopol (Carbopol, Feeder, supra, 1 , 206- 207), especially Carbopol products 934, 940 and 941, and Eudragit (Feeder, supra, see pages 1 , 372-373), especially Eudragit products E, L, S, RL and RS, most limited Eudragit products E, L and S.

d ² ) Cellulose and cellulose derivatives such as alkylcelluloses such as methyl-, ethyl- and propyl-celluloses, hydroxyalkyl-celluloses such as hydroxypropyl-celluloses and hydroxypropylalkyl-celluloses such as hydroxypropyl- Methyl-celluloses, acylated celluloses such as cellulose acetate, cellulose acetate phthalate, cellulose acetate succinate and hydroxypropylmethylcellulose phthalate and their salts such as sodium carboxymethylcellulose. Examples of said products suitable for use according to the invention are known and are commercially available, for example under the trade names Klucel and Methocel (Feeder, supra, pages 1 , 521 and 2 , page 601). See), in particular products such as Crucell LF, MF, GF and HF and Methocel K100, K15M, K100M, E5M, E15, E15M and E100M.

d ³ ) Polyvinylpyrrolidones, such as poly-N-vinylpyrrolidones and vinylpyrrolidone copolymers, such as vinylpyrrolidone-vinyl acetate copolymers. Examples of said compounds suitable for use according to the invention are known and are commercially available, for example under the trade name Kollidon (Feeder, supra, see pages 1 , 526 and 527), in particular the Kollidon products 30 and 90 There is.

d ⁴ ) Polyvinyl resins such as polyvinyl acetates and polyvinyl alcohols and other polymeric materials such as tragacanth gum, gum arabic, alginates such as alginic acid and salts thereof such as sodium alginate.

d ⁵ ) Silicon dioxides, such as hydrophilic silicon dioxide products, eg alkylated (eg methylated) silica gels, in particular known colloidal silicon dioxide products marketed under the trade name Aerosil [“Handbook of "Pharmaceutical Excipients", published by Pharmaceutical Society of Great Britain, pp. 253-256], especially Aerosil products 130, 200, 300, 380, O, OX50, TT600 , MOX80, MOX170, LK84 and methylated Aerosil R972.

  When component (d) is present, it is preferably about 0.5 to 50% by weight, more preferably about 1 based on the total weight of component (a) + (b) + (c) + (d). It is present in an amount of ˜20% by weight, most preferably about 2-10% by weight.

When component (c) in the composition of the invention comprises (c ⁶ ) a solid polymeric carrier as required by definition (vi) above, this is preferably a water-insoluble or substantially water-insoluble polymer. Sex carrier.

Particularly preferred as component (c ⁶ ) are polyvinyl pyrrolidones [Feeder, supra, 2 , pages 748-750], especially crosslinked polyvinyl pyrrolidones. Examples of those materials suitable for use in this invention are known, Kollidon [Feeder, supra, see page 1 , 527], Kollisept [Feeder, supra, page 2 , 719-720], Povidone and Crospovidone [Feeder, supra, 2 , page 751] are commercially available.

Particularly suitable components (c ⁶ ) are polyvinylpyrrolidones having a molecular weight of at least about 10,000, more preferably at least about 20000 or 25000, such as a molecular weight of about 40000 or higher. Of particular interest are crosslinked polyvinylpyrrolidones. Examples of specific products suitable for use in the present invention as (c ⁶ ) are Plasdone XL, Plasdon XL10 and Crospovidone.

Where the compositions of this invention comprise component (c ⁶ ), they also preferably comprise (d) a water-swellable or water-soluble component, such as cellulose or cellulose derivatives as defined in section (d ² ) above.

Further examples of those materials of particular interest with respect to the compositions of this invention comprising component (c ⁶ ) include Avicel (Feeder, supra, 1 , 160-161), Elcema [ Feeder, supra, page 1 , 326] and Pharmacoat (see Feeder, supra, page 2 , 707), known products such as Avicel PH101 and PH102, Elsema and Pharmacoat 603. There is a product.

In the case of the composition according to the invention comprising component (c ⁶ ), component (a) is present in component (b) which is a solid solution, for example a complete or substantially complete solid micelle solution, molecule or micelle dispersion. . [In practice, component (b) is not "solid" in the strictest sense, since it often exhibits at least some fluidity, for example at ambient or slightly elevated temperatures. Thus, the term “solid solution” as used herein, including the claims, should be interpreted as including, for example, viscous or highly viscous systems. (a) and (b) a solid solution of the components are preferably dispersed in the component (c ^6), for example, component (c ⁶⁾ across, for example, particles, for example, in particulate form. That is, component (c ⁶ ) generally functions as a disintegratable matrix for [(a) + (b)] in the compositions of this invention. Ingredient (d) generally functions as a disintegration aid upon contact with, for example, the contents of the gastrointestinal tract.

The composition of the invention comprising component (c ⁶ ) also preferably comprises (e) a binder and / or a lubricant. Binder / Materials suitable for use in lubricants, a fatty acid and alkyl sulfonates having a particular example the fatty acid / alkyl moiety 10 or more carbon atoms, for example, metal salts, for example C _{10 - 22} fatty acid and C _{10 - 22} alkyl sulfonic acid alkali metal or alkaline earth metal salts, such as sodium, calcium or magnesium salts. Examples of those materials suitable for use in this invention are sodium lauryl sulfate and magnesium stearate [see Feeder, supra, 2 , page 584].

When the composition of this invention includes component (c ⁶ ), components (a) and (b) are suitably about 1: 2-20, preferably about 1: 2.5-10, most preferably about 1: 3 to 8 [(a) + (b)].

Component (c ⁶ ) is present in the compositions of this invention suitably in an amount of at least 10% by weight, more preferably at least 15% by weight and more preferably at least 20% by weight relative to the total weight of the composition. . Preferably, component ^{(c 6)} is 10 to 60% by weight relative to the total weight of the composition, more preferably from 15 to 50 wt%, such as about 20 to 40 wt%, such as about 25, 30 or 35 weight Present in the composition of this invention in an amount of%.

When component (d) is present, component (d) and (c ⁶⁾ is suitably from about 1: 0.5-4, more preferably from about 1: 1 to 3, most preferably from about 1: 1. Present in a ratio [(d) :( c ⁶ )] of 5-2.5, for example about 1: 2 or about 1: 2.5 ppw.

If component (e) is present, component (e) and (c ⁶⁾ is suitably from about 1: 5 to 25, more preferably from about 1: 5 to 20, and most preferably about 1: the 7~15ppw It exists in the ratio [(e) :( c ⁶ )].
Composition three components of the present invention (c ^6), if it contains all the (d) and (e), they are preferably about 25-75% relative to the total weight of the composition, more preferably about 30 Are present together in an amount of ˜65%, most preferably about 40-65%. The component ratio [(a) + (b)]: [(c) + (d) + (e)] is preferably 1: 0.25 to 7.5, more preferably 1: 0.5 to 5. Most preferably, it is about 1: 0.5 to 2, for example, about 1: 0.8, 1: 1.2 or 1: 1.3 ppw.

The composition according to the invention comprising component (c ⁶ ) may be manufactured in any dosage form suitable for oral, parenteral or topical application, for example. Preferably, these compositions according to the invention are manufactured in unit dosage form, whether orally or by other methods of administration.

  Of course, the amount of component (a) present in these unit dosage forms will vary depending upon, for example, the condition being treated, the intended mode of administration and the desired effect. In general, however, they preferably contain from about 2 to about 200 mg of component (a), eg “cyclosporine”, per unit dose.

  Suitable dosage forms for oral administration include granules. However, preference is given to solid unit dosage forms such as tablets or capsules. Their oral unit dosage form is preferably about 5 to about 200 mg, more preferably about 10 or 20 to about 100 mg, for example 15, 20, 25, 50, 75 or 100 mg of component (a) per unit dose. For example, “cyclosporine”.

When component (c) in the composition of the present invention comprises (c ⁷ ) an organosilicon oxide polymer or super- or sub-liquid paraffin as required by definition (vi) above, component (c ⁷ ) is preferably Can easily flow at a temperature of 150 ° C. or lower, preferably 100 ° C. or lower, more preferably 50 ° C. or lower. Suitably component (c ⁷ ) has a maximum viscosity of 15000 mPa.s., more preferably 1000 mPa.s. at the indicated temperature.

Suitable paraffin hydrocarbons for use as component (c ⁷ ) are liquid and semi-solid paraffins and mixtures thereof, ie sub-liquid paraffins and superfluid paraffins [see Feeder, supra, 2 , pages 690-691]. . In order to facilitate formulation, component (c ⁷ ) is preferably constituted or essentially constituted by fluid or semi-solid paraffins, ie superfluid paraffin or sub-liquid paraffin or mixtures thereof. However, if it is desired to produce a composition with, for example, slower active ingredient release characteristics, this can be achieved by further adding solid paraffin, ie, durum paraffin.

If the composition according to the invention contains only liquid or semi-solid paraffins as component (c ⁷ ), these are preferably present in a ratio of about 1: 0.5 to 1.0 [liquid: semi-solid]. In this case, components (a) and (c ⁷ ) are suitably about 1: 6 to 200, more preferably about 1: 6 to 100, most preferably 1: 6 to 20, for example about 1: 8 ppw [( a) :( c)].

When the composition according to the invention additionally comprises solid paraffin as component (c ⁷ ), the ratio of liquid / semi-solid paraffin: solid paraffin component is preferably about 1: 0.06-0.1 ppw. In this case, components (a) and (c ⁷ ) are suitably from 1: 6 to 200, more preferably from 1: 6 to 100, most preferably from 1: 8 to 20, for example about 1:10 ppw [(a) : (c ⁷ )].

Organic silicon oxide polymers suitable for use as component (c ^7), in particular fluid, i.e. the formula -R ₂ Si-O- (wherein each R is a monovalent organic radical, for example C _{1 - 4} alkyl, in particular Liquid and semi-solid polymeric materials having structural units represented by (methyl or phenyl). Particularly preferred are organosiloxane polymers having a viscosity of about 0.65 to 10 ⁵ cP, especially about 10 or 50 to 500 or 1000 cP.

For ease of formulation, component ^{(c 7)} is preferably a liquid organosiloxane polymer, such as poly - methyl siloxane polymers, e.g., any of various known silicon oils, such as silicon oil 550, DC200, SF-1066 And SF-1091 [Feeder, supra, 2 , page 826]. When the composition according to the invention comprises only liquid organosiloxane polymer, components (a) and (c ⁷ ) are suitably about 1: 6 to 200, more preferably about 1: 6 to 100, most preferably 1 : 6 to 20, for example, a ratio [(a) :( c ⁷ )] of about 1: 8 ppw.

For example, a composition with slower active ingredient release properties may be used as component (c ⁷ ) as a semi-solid organosiloxane polymer, such as any of a variety of known silicon pastes, such as silicon paste A [Feeder, supra, 2 , page 826. Can be used, for example, or by adding them to other said organosilicon oxide polymers. In the latter case, the ratio of liquid: semi-solid organosilicon polymer present in the composition of this invention is preferably about 1: 0.5-1. In this case, the ratio of components (a) :( c ⁷ ) is suitably about 1: 6 to 100, preferably about 1: 6 to 20 ppw [(a) :( c ⁷ )].

Obviously, mixtures of said components (c ⁷ ) can also be used in the composition of the invention.
When the compositions of this invention comprise a component (c ^7), components (a) and (b) is suitably from about 1: 6 to 20, preferably from about 1: 6 to 10, and most preferably about 1: It is present in a ratio [(a) :( b)] of 6.0 to 6.5, for example, about 1: 6.25 ppw.

In the case of the composition according to the invention comprising component (c ⁷ ), component (a) is present in component (b) in the form of a molecule or micelle dispersion, eg solid solution or solid micelle solution, completely or substantially completely. [However, the term “solid solution” is used herein in the same broad sense as component (c ⁶ ) for the composition]. (a) and a solid solution composed of (b) is preferably dispersed with component (c ^7), for example, particles throughout the component (c ^7), for example in particulate form.

A composition according to the invention comprising component (c ⁷ ), for example for the treatment of the autoimmune condition of the eye, for example for the treatment of the aforementioned conditions, or for intralesional injection, for example for the treatment of psoriasis, for example oral, parenteral or topical application, For example, it may be manufactured in a dosage form suitable for dermatological or ophthalmic application, eg application to the surface of the eye. Suitably they are manufactured in unit dosage form, whether orally or other methods of administration.

  Of course, the amount of component (a) present in these unit dosage forms will vary depending upon, for example, the condition being treated, the intended mode of administration and the desired effect. In general, however, they preferably contain from about 2 to about 200 mg of component (a), eg "cyclosporine" per unit dose.

  Dosage forms suitable for oral administration include liquids, granules and the like. However, preference is given to solid unit dosage forms, such as tablets or encapsulated forms, in particular gelatin hard or soft capsule forms. Their oral unit dosage form is preferably about 5 to about 200 mg, more preferably about 10 or 20 to about 100 mg, for example 15, 20, 25, 50, 75 or 100 mg of component (a) per unit dose. For example, “cyclosporine”.

Compositions according to this invention comprising component (c ⁷ ) are those which have modified release characteristics, such as delayed release of component (a) or release of component (a) over time after oral administration. Another advantage is that it can provide a base for the resulting composition. These compositions can be prepared as described above by encapsulating the solid or semi-solid component (c ⁷ ) in an appropriate amount. Alternatively, they can be made by including additional component (d): a component that can modify the release characteristics of the composition with respect to component (a). These components (d) include, for example, polymeric excipients, especially thickeners, such as polymeric or colloidal thickeners, and agents that can swell in water, such as water-swellable polymers or colloids, such as those described above ( Any of the materials defined in the items d ¹ ) to (d ⁵ ) is included.

When component (d) is present, it is preferably about 0.5 to 30%, more preferably about 0.5%, based on the total weight of components (a) + (b) + (c ⁷ ) + (d) It is present in an amount of 1-20%, most preferably about 1-10%.

Component (d ⁵ ) is particularly suitable for use in the composition according to the invention comprising an organosilicon oxide polymer as component (c ⁷ ).
The composition according to the invention comprising component (c ⁶ ) or (c ⁷ ) is non-aqueous or substantially non-aqueous, for example as described above with reference to compositions comprising other components (c), or preferably That is the state.

The composition according to the present invention comprises a selected component (c) [eg, whether component (c) comprises any ^{one of the} aforementioned components (c ¹ ) to (c ⁷ ) or a mixture thereof] Regardless of the additive additive, for example known agents commonly used in the art, such as antioxidants [eg ascorbyl palmitate, tocopherols, butyl-hydroxy-anisole (BHA) or butyl-hydroxy-toluene (BHT)], flavoring agents and the like.

  In particular, the compositions according to the invention also preferably contain one or more stabilizers or buffering agents, in particular in order to prevent hydrolysis of component (b) or degradation of component (a), especially during processing steps or during storage. including. Such stabilizers may include acidic stabilizers such as citric acid, acetic acid, tartaric acid or fumaric acid, and basic stabilizers such as potassium hydrogen phosphate, glycine, lysine, arginine or tris (hydroxymethyl) aminomethane.

  These stabilizers or buffers are suitably added in an amount sufficient to achieve or maintain a pH in the range of about 3-8, more preferably about 5-7, such as 6-7. These stabilizers are generally present in amounts up to 5% by weight, or up to 10% by weight, based on the total weight of the composition, for example when citric acid or acetic acid is used. Compositions according to the invention having a pH in the above range are preferred, in particular those in which component (a) is “cyclosporine”.

  The composition according to the invention is also preferably a polyoxyalkylene-free surfactant such as dioctyl succinate, dioctyl-sulfo-succinate, di [2-ethylhexyl] -succinate, sodium lauryl sulfate or phospholipids such as lecithin Including. When present, the surfactant is suitably present in an amount of 5-50, more preferably 10-50, for example 10-25%, based on the weight of component (b).

In the case of the composition of the present invention containing the component (a) as a solid solution in the component (b), for example, when the component (c) is the aforementioned component (c ⁶ ) or (c ⁷ ), the aforementioned stabilizer and buffering agent And / or the surfactant is preferably incorporated into the solid solution phase. These materials can also be included in component (c) and the like.

  The composition according to the invention is also preferably ethanol-free or substantially free, independently of the selected component (c), for example less than 5.0% based on the total weight of the composition, Preferably it contains less than 2.5% ethanol, for example 0-1.0% ethanol.

  In addition to the above contents, the present invention also provides a method for producing the pharmaceutical composition, wherein the components (a), (b) and (c) are optionally mixed with component (d) and / or other components, For example, intimate mixing or formulation with the aforementioned stabilizers, buffers or surfactants, and if necessary, the resulting composition may be unit dosed, for example, by tableting, filling into gelatin capsules or other suitable means. A method is provided that comprises formulating a form, eg, a unit dosage form for oral administration.

When component (c) is a solvent for components (a) and (b) or contains component (c ¹ ), (c ² ), (c ³ ), (c ⁴ ) or (c ⁵ ) , Components (a), (b) and (c) are suitably combined with components (a) and (b) while warming at a temperature not exceeding 50 ° C. to 150 ° C., preferably not exceeding 70 or 75 ° C. Are combined in the above process by dissolving in component (c). The mixture thus obtained can then be further mixed with component (d) etc., for example by intimate mixing according to techniques known in the art. For example, gelatin hard or soft capsules are preferably filled at a high temperature, for example 50 ° C. or less, to achieve fluidity of the composition, for example in warm air.

In the case of a composition according to the invention comprising component (a) as a solid solution in component (b), for example a composition comprising component (c ⁶ ) or (c ⁷ ) as described above, the method is preferably first (b ) Producing a solid solution containing (a) in the middle and then intimately mixing or blending the resulting solid solution with the remaining component (c) and optionally (d) and the like.

  The solid solution containing the component (a) in (b) is solidified according to a known technique in the art, for example, by solidifying a melt containing (a) in (b), or components (a) and (b ) To remove the solvent from the solution. For the purposes of this invention, the latter method is generally preferred.

  Solvents for components (a) and (b) include alkanols such as ethanol. Stabilizers, buffers and / or surfactants are preferably incorporated during the dissolution stage.

  Next, the solid solution thus obtained is preferably mixed with the component (c) and optionally the components (d) and (e), for example, in the form of fine particles, for example, by distributing it to the component (c).

  Ethanol can be used for the purpose of producing the composition of the invention, for example in the production of the solid solution, but this is preferably removed, for example by evaporating prior to completion of the final dosage form, so that the aforementioned ethanol A product free or substantially free of ethanol is obtained.

Hereinafter, the present invention will be described by way of examples.
The product saccharose monolaurate L-1695 used in the examples is commercially available from Mitsubishi Kasei Food Company (Tokyo 104, Japan). HLB value = at least 12.3, lauryl ester residue purity = at least 95%, MP = about 35 ° C, decomposed at about 235 ° C, surface tension of 0.1 wt% aqueous solution = about 72.0 dyn / cm at 25 ° C.

Example ingredients Relative amount (mg)
1.a) Cyclosporine (eg “cyclosporine”) 50.0
b) Saccharose monolaurate L-1695 312.5
c) 1,2-propylene glycol 100.0
Total 462.5

2.a) Cyclosporine (eg “cyclosporine”) 50.0
b) Saccharose monolaurate L-1695 312.5
c) Glycerin 100.0
Total 462.5

3.a) Cyclosporine (eg, “cyclosporine”) 50.0
b) Saccharose monolaurate L-1695 312.5
c) PEG200 100.0
Total 462.5

4.a) Cyclosporine (eg “cyclosporine”) 50.0
b) Saccharose monolaurate L-1695 312.5
c) PEG400 100.0
Total 462.5

5.a) Cyclosporine (eg “cyclosporine”) 50.0
b) Saccharose monolaurate L-1695 350.0
c) 1,2-propylene glycol 100.0
d) Eudragit E 50.0
Total 550.0

6.a) Cyclosporine (eg “cyclosporine”) 50.0
b) Saccharose monolaurate L-1695 350.0
c) 1,2-propylene glycol 100.0
d) Methocel K100 110.0
Total 610.0

7.a) Cyclosporine (eg “cyclosporine”) 50.0
b) Saccharose monolaurate L-1695 350.0
c) 1,2-propylene glycol 100.0
d) Aerosil 200 15.0
Total 515.0

8.a) Cyclosporine (eg, “cyclosporine”) 50.0
b) Saccharose monolaurate L-1695 350.0
c) PEG400 20.0
d) Eudragit L 2.5
Total 602.5

9.a) Cyclosporine (eg “cyclosporine”) 50.0
b) Saccharose monolaurate L-1695 312.5
c) Gelsil (e.g. Gelsil 42/12,
44/14 or 35/10) 100.0
Total 462.5

10.a) Cyclosporine (eg “cyclosporine”) 50.0
b) Saccharose monolaurate L-1695 312.5
c) Gelsil 100.0
d) Crucell LF 50.0
Total 512.5

  The composition of Example 1 is prepared by dissolving components (a) and (b) with stirring and warming in component (c) in an oil bath at 100 ° C. The compositions of Examples 2 to 10 are produced in the same manner. In the case of Examples 5 and 8, component (d) is dissolved in the initially obtained mixture of components (a) to (c). In the case of Examples 6, 7 and 10, component (d) is suspended in (a)-(c).

  Filling the resulting composition into hard gelatin capsules, size 1 (Examples 1 to 4 and 9) or size 0 (Examples 5 to 7 and 10) while warming yields the final product encapsulated in the capsule. It is done. Each capsule contains 50 mg of cyclosporine (eg, “cyclosporin”) and is suitable for administration in the prevention of transplant rejection or in the treatment of autoimmune diseases, eg administration of 1 to 5 capsules per day.

Example ingredients Relative amount (mg)
11.a) Cyclosporine (eg “cyclosporine”) 100.0
b) Saccharose monolaurate L-1695 300.0
c) Plusdon XL 350.0
d) Avicel PH102 150.0
e) Sodium lauryl sulfate 25.0
Total 925.0

12.a) Cyclosporine (eg “cyclosporine”) 50.0
b ¹ ) Saccharose monolaurate L-1695 350.0
b ² ) Saccharose monostearate 50.0
c) Crospovidone 250.0
d) Elsema 150.0
e) Magnesium stearate 30.0
Total 980.0

13.a) Cyclosporine (eg “cyclosporine”) 50.0
b) Saccharose monolaurate L-1695 160.0
c) Plusdon XL10 20.0
d ¹ ) Pharmacoat 603 25.0
d ² ) Avicel PH101 75.0
e) Magnesium stearate 20.0
Total 605.0

  The compositions 11-13 preferably each further comprise 25 mg (f) tartaric acid and / or 50 mg (g) dioctyl succinate, preferably both, with a final weight of 1000 mg for composition 11, composition In the case of the product 12, it is 1055 mg, and in the case of the composition 13, it is 6180 mg.

  The compositions 11-13 are manufactured in the following manner. Components (a) and (b) are dissolved in absolute ethanol and the ethanol is thoroughly evaporated at 50 ° C. under reduced pressure. Thoroughly mix components (c)-(e) using conventional mixing techniques [add these if (f) and (g) are used]. The solid solution containing [(a) + (b)] is crushed into a fine powder and mixed uniformly into [(c)-(g)], and the resulting uniform mass is added to 100, 50 or 25 mg of ( a) and compressed into tablets suitable for administration in the prevention of transplant rejection or in the treatment of autoimmune diseases, eg 1-5 tablets per day.

Example ingredients Relative amount (mg)
14.a) Cyclosporine (eg “cyclosporine”) 50.0
b) Saccharose monolaurate L-1695 312.5
c) Superfluid paraffin 397.5
Total 760.0

15.a) Cyclosporine (eg “cyclosporine”) 50.0
b) Saccharose monolaurate L-1695 312.5
c) Silicon oil DC200 397.5
Total 760.0

  Components (a) and (b) are dissolved in absolute ethanol and the ethanol is thoroughly evaporated at 50 ° C. under reduced pressure. The obtained solid solution is pulverized into a fine powder and uniformly suspended in the component (c). The resulting liquid suspension is filled into gelatin hard capsules, size 0, to obtain the final product encapsulated. Each capsule contains 50 mg of cyclosporine (eg, “cyclosporine”) and is suitable for administration in the prevention of transplant rejection or in the treatment of autoimmune diseases, eg administration of 1 to 5 capsules per day.

Example ingredients Relative amount (mg)
16.a) Cyclosporine (eg “cyclosporine”) 50.0
b) Saccharose monolaurate L-1695 312.5
c) Sub-liquid paraffin 372.5
d) Solid paraffin 25.0
Total 760.0

17.a) Cyclosporine (eg “cyclosporine”) 50.0
b) Saccharose monolaurate L-1695 312.5
c) Superfluid paraffin 397.5
d) Aerosil 10.0
Total 770.0

  Compositions 16 and 17 are also produced in the same manner as 14 and 15 above. In the case of the composition 16, first, the components (c) and (d) are combined by dissolving them, and they are stirred together closely. Next, the solid solution containing [(a) + (b)] is suspended in [(c) + (d)]. In the case of composition 17, (d) is suspended in (c) together with [(a) + (b)].

Compositions equivalent to the compositions of Examples 1 to 17 described above replace “cyclosporine” as component (a) with another cyclosporine, for example [Nva] ^2- “cyclosporin”, or saccharose as component (b). It can be prepared by replacing monolaurate with, for example, the other fatty acid saccharide monoesters mentioned above, such as raffinose monolaurate, but in each case in the same or equivalent amounts or relative proportions.

The usefulness of the composition according to the invention can be demonstrated, for example, in animal or clinical trials carried out as follows.
Bioavailability test for the composition of this invention in dogs.

a) Test composition Composition I according to Example 1
Composition II according to Example 14
b) Test method A group consisting of 8 beagle dogs (male, approximately 11-13 kg) is used. The animals are not fed within 18 hours of administration of the test composition, but are allowed free access to water until the time of administration. The test composition is administered by gavage followed by 20 ml of a 0.9% solution of NaCl. Three hours after administration of the test composition, the animals are allowed free access to food and water.

  Two ml blood samples (or 5 ml if blank) are taken from the saphenous vein and -15 minutes (blank), 30 minutes, and 1, 1.5, 2, 3, 4, 6, 8, 12, and After 24 hours, collect in a 5 ml plastic tube containing EDTA. Blood samples are stored at -18 ° C until the assay is performed.

  Blood samples are analyzed by RIA. Calculate the area under the blood drug concentration vs. time curve according to the trapezoidal rule. Analysis of the amount of dispersion is performed with respect to AUC (area under the curve), Cmax (maximum concentration) and Tmax (maximum time).

c) Results The mean AUC (ng · hr / ml ⁻¹ ) and C max (ng / ml ⁻¹ ) values calculated from the representative study course were calculated in response between the test animals administered the same composition. It is shown in the table below together with the rate (CV).

Composition AUC CV (%) Cmax CV%
(0-24 o'clock)
I 3058 19.9 583 30.9
II 2894 14.91 544 19.7

  As is apparent from the table above, the composition according to the present invention exhibits high bioavailability (AUC and Cmax) associated with relatively low variability in the subject response for both AUC and Cmax.

  Advantageous results comparable to these are obtained with other compositions according to Examples 1-17 above, in particular with the compositions of Examples 1-10.

The advantageous properties of the composition of the invention for oral administration in clinical trials can also be demonstrated in clinical trials conducted, for example, as follows.
The test subjects are adult volunteers, such as men aged 30 to 55 years with professional education. The test group is preferably composed of 12 subjects.

The following inclusion / exclusion criteria apply:
Inclusion: normal screening ECG, normal blood pressure and heart rate, body weight = 50-95 kg.
Exclusions: Clinically significant interventional medical conditions that may conflict with drug absorption, distribution, metabolism, excretion or safety, signs of clinically significant disease in the 2 weeks prior to the study, clinically meaningful abnormal experimental values Or electrocardiogram, the need for concomitant medical care throughout the study, administration of drugs known to have well-defined potential toxicity to major organ systems within 3 months prior to study, 6 weeks prior to study initiation Study drug administration within, history of drug or alcohol dependence, loss of blood of 500 ml or more in the past 3 months, drug side effects or hypersensitivity, history of allergy requiring drug treatment, hepatitis B / HIV positive .

A complete physical examination and ECG will be performed before and after the test. The following parameters are evaluated within one month before and after the test.
Blood:-Red blood cell count, hemoglobin, hematocrit, erythrocyte sedimentation, white blood cell count, smear, platelet count and fasting glucose.

Serum / plasma-total protein and electrophoresis, cholesterol, triglycerides, Na ⁺ , K ⁺ , Fe ⁺⁺ , Ca ⁺⁺ , Cl ⁻ , creatinine, urea, uric acid, SGOT, SGPT, −GT, alkaline phosphatase, total bilirubin, α-amylase.
Urine-pH, microalbumin, glucose, erythrocytes, ketone bodies, precipitates.

Creatinine clearance is measured one month before the start of the test.
Each subject is given the test composition in a random order. The composition is administered orally (a total dose of 150 mg of cyclosporine, eg “cyclosporine”), with at least 14 days between each administration.

  Dosing in the morning after an overnight fast of 10 hours (but only water is allowed). Only caffeine-free beverages are allowed within 24 hours after administration. The subject does not smoke within 12 hours after administration. Four hours after dosing, subjects are given a standard lunch.

  1 hour before administration and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 9, 12, 14, Blood samples (2 ml) are taken after 24, 28 and 32 hours. To measure creatinine, 2 ml blood samples are taken immediately before dosing and at 12, 24 and 48 hours after dosing. Samples for cyclosporine determination are collected in two EDTA-coated polystyrene tubes (1 ml each) at each time point and gently frozen at −20 ° C. after gentle stirring. Cyclosporin in whole blood is measured using RIA with specific and / or non-specific MAB assay. Detection limit in both cases = about 10 ng / ml.

  In a test carried out according to the above protocol, for example, the composition of Example 1 in gelatin hard capsule form, as a standard, “Cyclosporin” drinking liquid (“Cyclosporin” = 50 mg, Labrafil = 150 mg, ethanol = 50 mg, corn oil = 213 mg, As compared to the standard, Example 1 as reflected in both the established AUC (0-32 hours) and Cmax values compared to the final weight of the content = 463 mg / dose in gelatin soft capsule form) A significant increase in the level of bioavailability has been recorded for the present compositions. In addition, all subjects who received the standard composition compared the change in whole blood “cyclosporin” concentration over time (measured by specific monoclonal RIA) after a single administration of the test composition (150 mg “cyclosporine” dose). It is demonstrated that the variability of response between all subjects receiving the composition according to Example 1 is significantly reduced compared to

Similar or equivalent results are obtained after oral administration of other compositions according to this invention, such as those described in the Examples.

Claims (11)

(a) cyclosporine as an active ingredient in the solid solution,
(b) a fatty acid saccharide monoester, and
(c ⁶⁾ a pharmaceutical composition comprising a solid polymeric carrier. Component (c ⁶⁾ comprises a polyvinylpyrrolidone composition of claim 1.   The composition according to claim 1 or 2, wherein components (a) and (b) are present in a ratio of 1: 2 to 20 ppw [(a) :( b)].   The composition of claim 3, wherein the ratio is from 1: 3 to 8 ppw. Component (c ⁶⁾ is present in an amount of at least 10 wt% based on the total weight of the composition, any one composition according to claims 1-4. ^{6. A} composition according to claim 5, wherein component (c6) is present in an amount of 15 to 50% by weight, based on the total weight of the composition.   The composition according to any one of claims 1 to 6, further comprising (d) a water-swellable component. Component (d) and (c ⁶⁾ is, 1: 0.5~4ppw present in proportions ^{[(d) :( c 6)} ], composition of claim 7.   9. A composition according to any one of the preceding claims comprising 2 to 200 mg of component (a) per unit dose in unit dose form.   Furthermore, the composition of any one of Claims 1-9 containing a stabilizer or a buffering agent. (a) cyclosporine as an active ingredient,
(b) a fatty acid saccharide monoester, and
(c) a pharmaceutical composition containing a diluent or carrier,
(i) component (c) is a solvent for both components (a) and (b), and components (a) and (b) each independently have a solubility of at least 10% in component (c) at ambient temperature Have or
(ii) Component (c) is a solvent for both components (a) and (b), and components (a) and (c) are 1: 0.5-50 ppw [(a) :( c )], Or
(iii) component (c) is a solvent for both components (a) and (b) and the composition is formulated in a solid unit dosage form suitable for oral administration, or
(iv) component (c), poly has a viscosity of 15000mPa.s most at temperatures of average molecular weight or 50 ° C. of 7000 at most -. (C _{2 - 4} alkylene) - or glycols, or C _{3 -} Contains ₅ alkylene polyol ethers or esters, or
(v) the composition is less than 20% water based on its weight, or
(vi) component (c) comprising a solid polymer carrier, an organosilicon oxide polymer or a per- or sub-liquid paraffin, wherein component (a) is a solid solution in component (b) Present in the
Composition.