JP2001302538A - New pharmaceutical preparation of cyclosporine - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a new pharmaceutical preparation including cyclosporine as an active ingredient. SOLUTION: This pharmaceutical preparation includes (a) the cyclosporine as the active ingredient, (b) a fatty acid monosaccharide ester and (c) a diluent or a substrate.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

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

[0002]

BACKGROUND OF THE INVENTION Cyclosporins are a class of structurally unique cyclic poly-N-methylated endecapeptides which usually have pharmacological, especially immunosuppressive, anti-inflammatory and / or antiparasitic activity. Is included. The first of the cyclosporins to be isolated was the natural fungal metabolite `` cyclosporin '' (Ciclosporin or Cyclosporine), also known as cyclosporin A and marketed under the trade name Sandimmun or Sandimmune. . “Cyclosporin” has the formula (A)
Is a cyclosporin represented by

[0003]

Embedded image [In the formula, -MeBmt- is the formula (B)

Embedded image (Wherein -x-y- is -CH = CH- (trans)) represented by N-methyl- (4R) -4-buta-2E-ene-
Represents a 1-yl-4-methyl- (L) threonyl residue]

As a parent of this type, "cyclosporin"
Has received the most attention so far. The main area of clinical research on "cyclosporine" is as an immunosuppressant, especially for recipients of 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 remarkable achievements and reputation in this field.

At the same time, the use of "cyclosporine" for various autoimmune diseases and inflammatory conditions, in particular inflammatory conditions of etiology involving autoimmune components, such as arthritis (eg rheumatoid arthritis, chronic progressive arthritis and osteoarthritis) and rheumatic diseases. The applicability is very strong, in vitro,
Reports and results in animal models and clinical trials have been extensively described in the literature. Specific autoimmune diseases for which "cyclosporin" therapy has been proposed or applied include:
Autoimmune blood disorders (including, for example, hemolytic anemia, aplastic anemia, congenital aplastic anemia and idiopathic thrombocytopenia), systemic lupus erythematosus, polychondritis, scleroderma, Wegener's granulomatosis, skin Myositis, chronic active hepatitis,
Myasthenia gravis, psoriasis, Steven-Johnson syndrome, idiopathic sprue, autoimmune inflammatory bowel disease (e.g.,
(Including ulcerative colitis and Crohn's disease), endocrine eye disease, Graves' disease, sarcoidosis, multiple sclerosis,
Primary biliary cirrhosis, juvenile diabetes mellitus (diabetes mellitus type I),
Uveitis (anterior and posterior), keratoconjunctivitis sicca and spring, keratoconjunctivitis interstitial, psoriatic arthritis and glomerulonephritis (e.g., with nephrotic syndrome, including idiopathic nephrotic syndrome or micronephrotic nephropathy) Or without).

[0006] Another area of research is the potential application as antiparasitics, particularly as antiprotozoal agents, and possible applications including the treatment of malaria, coccidioidomycosis and schistosomiasis, more recently It has been suggested for use in treating cancer as an agent that lifts or eliminates resistance to antineoplastic or cytostatic therapies.

Since the initial discovery of cyclosporine, a wide range of natural cyclosporins have been isolated and identified,
Many further unnatural cyclosporins have been produced by application of whole or semi-synthetic means or modified culture techniques. That is, the types encompassed by cyclosporins are abundant, for example, natural cyclosporins A to Z [reference,
Travers, etc., 1, "Helvetica Simika Acta" (Hel
v. Chim. Acta.) 60 , 1247-1255 (197
7), Travers, etc., 2, "Helvetica Simica Acta" (Helv. Chim. Acta.) 65 , number 162, 165
5-1667 (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," 3
8 , 28-45 (1986)], as well as various unnatural cyclosporin derivatives and artificial or synthetic cyclosporins, such as so-called dihydro-cyclosporins [where the -xy- portion of the -MeBmt- residue (formula B above) ) by saturating _{the, -x-y - = - CH} 2 -CH 2 -
Are obtained], derivatized cyclosporins (e.g., α- of the sarkosyl residue at the 3-position of the cyclosporin molecule is substituted with another substituent)
Cyclosporins in which the -MeBmt- residue is present in isomeric form (e.g., when the configuration between the 6 'and 7'-positions of the -MeBmt- residue is cis rather than trans). And cyclosporins in which variant amino acids are incorporated at specific positions in the peptide sequence [e.g., Traver 1, Traver 2 and Corbel, supra, U.S. Pat. 410898
No. 5, No. 4210581 and No. 4220641
No., European Patent Publication No. 0034567, 00
56782 and 0296122, International Patent Publication No. WO 86/02080, Wenger 1, "Transplantation Proceedings" (Transp. Pr.
oc.) 15 , Addendum 1: 2230 (1983), Wenger 2, "Angevante Chemie International Edition in English" (Angew. Chem. In).
t. Ed.), 24 , 77 (1985) and Wenger 3,
"Progress in the Chemistry of Organic Natural Products"
emistryof Organic Natural Products), 50 , 123
(1986)].

That is, species contained in cyclosporins
For example, [Thr]²-, [Val]²-, [Nva]²
-And [Nva]²-[Nva]⁵− `` Cyclosporine '' (each
Also known as cyclosporins C, D, G and M
), [3'-O-acyl-MeBmt]¹-"Cyclospo
Phosphorus ”(also known as cyclosporin A acetate)
), Dihydro- [MeBmt]¹− [Val]²-"Cyclospo
Phosphorus "(also known as dihydro-cyclosporin D)
3) -desoxy-3'-oxo- [MeBmt]¹−
[Val]²-And-[Nva]²-"Cyclosporine",
[(D) Fluoromethyl-Sar] ³-"Cyclosporin",
[(D) Ser]⁸-"Cyclosporine", [MeIle]¹¹−
Crossporin ", [(D) MeVal]¹¹-"Cyclosporine"
(Also known as cyclosporin H), [MeAla]
⁶-"Cyclosporine", [(D) Pro]³-"Cyclospoli
".

[According to the current customary nomenclature for cyclosporins, they are defined on the basis of the structure of "cyclosporin" (ie cyclosporin A). This indicates an amino acid residue different (existing) from the amino acid residue present in “cyclosporin” (eg, “[(D) Pr
o] ³ "indicates that the cyclosporin in question has-(D) Pro-, rather than a -Sar-residue, at position 3) and then exists in" cyclosporin "by applying the term" cyclosporin " This is done by characterizing the remaining residues that match those residues. For each residue, the residue at position 1 -M
Numbering starts with eBmt-, -dihydro-MeBmt- or its equivalent. ]

[0010] Furthermore, a great number of these cyclosporins exhibit pharmaceutical or even more specific utility comparable to "cyclosporin", for example, an activity to counteract tumor resistance, especially to cytostatic therapy, and are useful as therapeutic agents. There are many proposals in the literature regarding their applicability.

Although "cyclosporine" has made a very large contribution, especially to the area of organ transplantation and the treatment of autoimmune diseases, the difficulties and undesirable side effects encountered in providing more effective and convenient means of administration, especially The reported occurrence of a nephrotoxic reaction is an obvious and serious obstacle to its widespread use or application. Cyclosporins are characterized by high hydrophobicity. For example, liquid formulations proposed for oral administration of cyclosporins are:
Heretofore, it has been mainly based on the use of ethanol and oils or similar excipients as carrier media. That is, the commercially available "cyclosporin" drinking liquid uses ethanol and olive oil as a carrier medium together with Labrafil (registered trademark) as a surfactant (for example, see US Pat. No. 4,388,307). However, the use of drinking liquids and similar compositions that have been proposed in the art involves a variety of difficulties.

First, the need to use oils or oil-based carriers can add unpleasant taste to the formulation, or otherwise degrade the mouthfeel, especially for long-term therapeutic purposes. . These effects may be masked by formulating them in a gelatin capsule form. However, to maintain cyclosporin in solution, the ethanol content must be kept high. When opened, for example, a precipitate of cyclosporin appears as a result of evaporation of the ethanol, for example from capsules or other forms. When these compositions are formulated, for example, in the form of soft gelatin capsules, this particular problem requires that the product be packaged in an airtight compartment, for example an airtight blister or an aluminum foil blister. As a result, the product is bulky and expensive to manufacture. The storage properties of the above formulations are far from ideal.

[0013] The level of bioavailability achieved with existing oral cyclosporine dose systems is also low, and varies widely between individuals, between individual patient types and at different times during the course of treatment, even for single individuals. Present. That is, reports in the literature indicate that currently available therapies with commercially available "cyclosporine" drinking solutions provide only about 30% of the average absolute bioavailability, and between individual groups, such as liver ( (Low bioavailability) and bone marrow (high bioavailability) exhibit significant variability among transplant recipients. It has been reported that the range of variation in bioavailability between subjects can be as low as one or a few percent, and even up to 90% or more, depending on the patient. And, as already mentioned, significant changes over time in bioavailability for individuals are frequently observed.

In order to achieve an effective immunosuppressive treatment, the blood or serum levels of cyclosporin must be maintained within certain ranges. In this case, the scope required is the particular condition to be treated, e.g., whether the treatment is for the prevention of transplant rejection or control of an autoimmune disease, or for another immunosuppressive therapy, cyclosporine. It may vary depending on whether it is used concurrently with therapy. Because of the widely varying levels of bioavailability achieved with conventional dosage forms, the daily dose required to achieve the required serum levels also varies considerably between individuals and for single individuals. I do. For this reason, it is necessary to monitor blood / serum levels in patients receiving cyclosporine therapy at regular and frequent intervals. Monitoring of blood / serum levels, which is generally performed using RIA or equivalent immunoassay techniques, for example, science and technology based on monoclonal antibodies, must be performed on a regular basis. This is necessarily time consuming and inconvenient, adding substantially to the overall cost of the treatment.

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

Various proposals have been suggested in the art to overcome those problems, including both solid and liquid oral dosage forms. That is, Japanese Patent Application No. Sho 60-71682 by Takada et al.
No. 435) shows the application of a means to increase the lymph gland delivery of cyclosporins, specifically by administration in combination with a surfactant. A general list of surfactants that can be used includes saccharose (sucrose) fatty acid esters such as saccharose oleate, palmitate or stearate, and other fatty acid esters, especially sorbitan fatty acid esters such as sorbitan oleate, palmitate Or include stearate. Although the use of both mono- and poly-esters is indicated, mono- or di-esters are generally suggested as preferred. Other surfactants listed include polyoxyethylated hydrogenated vegetable oils, such as the known products marketed under the trade names Cremophor RH and Nikkor HCO60, which obviously include, for example, the saccharose ester interface described above. It has been shown to be preferred over activators.

The embodiment 3 of the Japanese application is based on
Saccharose fatty acid, identified as F160,
It describes how to obtain an aqueous formulation containing stell. this
The formulation is 1 ml of H₂3.5mg of "cyclosporin" in O
And 2 mg of sucrose ester. "S
100W for 5 minutes to achieve "Crosporin" dispersion
Sonication is required. Described as "clear solution"
Use the obtained preparation directly in animal models.
To investigate relative lymph gland absorption. H ₂To O
Low solubility of "cyclosporin" in
If a small amount of surfactant is used, the claimed solution
Clearly, it is an artifact of the wave treatment method. Achievement
The "cyclosporin" concentration given for example for oral dosage forms
Improperly low and this formulation is inherently unstable
Therefore, any kind of commercial or commercial formulation
Have been virtually eliminated. It is essentially a laboratory lab
It is just an experimental system that enables research. Lymph gland delivery
Surface activity in any other part of the specification except for
The use of agents is not proposed.

Japanese Patent Application No. 62-1 by Takada et al.
No. 93129 (Japanese Patent Application Laid-Open No. 1-038029) discloses, for example, sucrose, sorbitol,
Disclosed are powder formulations containing cyclosporin dispersed in a solid non-surfactant carrier phase comprising tartaric acid, urea, cellulose acetate phthalate, methacrylic acid / methyl methacrylate or hydroxypropyl methylcellulose phthalate. In addition, a surfactant is added together with an object to enhance the lymph gland delivery, and in the meaning of this specification, this application is clearly based on the aforementioned Japanese Patent Application No. 60-7 / 1985.
It is intended to provide practical means intended to apply the teachings of 1682. Saccharose esters as possible surfactant components have been omitted in this case. Of the list of possible surfactants, sorbitan esters are reserved. However, Nikkor HCO60 type products have also been shown to be preferred as surfactants, and Nikkor HCO60 is the only surfactant used in the examples. The claimed 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 ever faced .

[0019]

The present invention provides a novel cyclosporin preparation containing a fatty acid saccharide monoester as a main carrier component. These solve or substantially reduce the problems with cyclosporin, eg, "cyclosporin" therapy, which the art has hitherto encountered. In particular, the compositions of the invention allow for the production of solid, semi-solid and liquid compositions containing cyclosporin, for example, at a concentration high enough to allow for conventional oral administration, while at the same time having, for example, bioavailability properties. Have been found to achieve improved efficacy.

More particularly, the composition according to the invention simultaneously increases the level of absorption / bioavailability and
In individual patients receiving cyclosporine therapy,
It has been found that it allows for effective cyclosporine administration that reduces the variability in the level of absorption / bioavailability achieved, both for and between individuals. By applying the teachings of this invention, it is possible to obtain cyclosporin dosage forms that reduce the variability in cyclosporin blood / serum levels achieved between doses for individual patients and between individuals / individual patient groups. That is, the present invention
It allows for a reduction in the cyclosporin dose levels required to achieve effective treatment. Further, the present invention allows for more precise standardization and optimization of ongoing daily dose requirements for individual subjects receiving cyclosporine therapy and for groups of patients who are receiving equivalent treatment.

By more precisely standardizing dose ratios and blood / serum level responses of individual patients, and dose and response parameters for a group of patients, monitoring requirements can be reduced, ie, substantially reducing the cost of treatment. Can be.

By reducing the required dose of cyclosporine / standardizing the bioavailability characteristics achieved, the present invention also provides for the reduction of unwanted side effects, especially nephrotoxic reactions, in patients receiving cyclosporine therapy. Means can be provided to reduce the occurrence.

The present invention further allows the preparation of compositions which are non-alkanol-based, for example, may be free or substantially free of ethanol. Their composition is
It avoids the aforementioned stability and related processing problems inherent in known alkanol compositions. That is, the present invention is more particularly suited for formulation as, for example, capsules, for example as hard or soft gelatin capsules, and / or
Alternatively, there is provided a composition that eliminates or substantially reduces packaging problems, e.g., as described above with respect to, e.g., soft gelatin encapsulated forms.

More specifically, the present invention comprises: a) cyclosporin as an active ingredient, b) a fatty acid saccharide monoester and c) a diluent or carrier, wherein (i) component (c) comprises components (a) and ( solvent for both of b), wherein components (a) and (b) each independently have a solubility of at least 10% in component (c) at ambient temperature,
Alternatively, (ii) component (c) is a solvent for both components (a) and (b), and components (a) and (c) are 1: 0.
5 to 50 ppw [(a) :( c)] or (i)
ii) 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) ) But at most 7
000 average molecular weight or at most 15000 mPa.s.
Poly has a viscosity at 50 ° C. of - _{(C 2} - ₄ alkylene) -
Or glycols or C _{3 - 5} alkylene polyol or an ether or ester, or, (v)
The composition is non-aqueous, or substantially non-aqueous;
Alternatively, (vi) component (c) comprises a solid polymer carrier, an organo-silicon oxide polymer or a paraffinum per-liquidum or a sub-liquid paraffin (paraffinum sub-liquidum). , Wherein the component (a) is present in the composition as a solid solution in (b).

The compositions defined above are described in French Patent Application No. 8811953 and USSN 07/2.
43577, DOS No. 3830945, Japanese Patent Application No. 63-231396, and British Application No. 882.
1443.9 (first published in France, 198
No. 2620336, Mar. 17, 9), a new and particularly advantageous modification of the subject matter alleged comprehensively in corresponding applications in other world countries.

The above definitions (i) to (vi) should be understood as being compatible with each other. That is, the compositions of the present invention include compositions defined according to any one or more of the defined limitations (i)-(vi). That is, preferred compositions according to the present invention include, for example, (i) to
(v).

[0027] The term "pharmaceutical composition" as used herein, including the claims, refers to a composition as defined, wherein the individual components or ingredients are themselves pharmaceutically acceptable. It should be understood that, for example, if oral administration is expected, it is acceptable for oral use, or if local administration is expected, it is acceptable for topical use.

A preferred cyclosporin as component (a) is "cyclosporine". More preferred component (a)
Is also known as cyclosporin G [Nva] ^2-
"Cyclosporine".

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

The fatty acid portion of component (b) may be saturated or unsaturated.
It may comprise a sum fatty acid or a mixture thereof. Especially suitable
Component (b) is C₆-₁₈Fatty acid saccharide / monoester
, Especially water-soluble C₆-₁₈Fatty acid saccharide monoes
Tells. Particularly suitable component (c) is caproic acid
(C₆), Caprylic acid (C₈), Capric acid (C₁₀), Lau
Lylic acid (C₁₂), Myristic acid (C₁₄), Palmitic acid
(C₁₆), Oleic acid (C ₁₈), Ricinoleic acid (C₁₈)
And 12-hydroxystearic acid (C₁₈) Sacchari
Monoesters, especially lauric saccharide mono
Esters.

The saccharide moiety of component (b) may contain a suitable sugar residue, for example, a mono-, di- or tri-saccharide residue. Suitably, the saccharide moiety comprises a di- or tri-saccharide residue. Preferred component (b) is C _6-
14 fatty acid di - saccharide monoesters and _{C 8} -
Includes ₁₈ fatty acid tri-saccharide monoesters.

[0032] 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 monolisinoleate, raffinose monocaproate, raffinose monolaurate, raffinose. Monomyristate, raffinose monopalmitate and raffinose monooleate. 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) is
Suitably it 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 about 15C to about 60C, more preferably about 25C to about 50C.

The above definition as applied to the composition of the invention
According to (ii) and (iii), defined component (c) is (a)
Both components (b) and (b) are materials that exhibit considerable solubility at ambient temperature, for example at a temperature of about 20 ° C. Preferred ingredients
(c) means that (a) and (b) are independently at least 10% at ambient temperature [required by definition (i)], preferably at least 25%, most preferably at least 50% (e.g. the components (a) or (b) is independently at least 100 m
g, preferably 250 mg, most preferably at least 5
(With a solubility of about 00 mg / ml). Particularly preferred material conditions include component (a)
But at least 10%, preferably at least 25%,
Most preferably having a solubility of 50%, and / or
Alternatively, when component (b) has a solubility of at least 100%, more preferably at least 200%, most preferably at least 300% (eg, component (b) has a solubility of at least 1000, more preferably 2000, most preferably At least about 3000 mg / ml).

The components suitable for use in the compositions of the present invention (c) 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 the invention, the use of ethanol, either alone or in admixture with any other component (c), is generally less preferred.

[0037] Component (c) is _{C 2 - 4} alkylene glycol (c
When comprising ² ), this is preferably propylene glycol, 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.

[0038] Component (c) is poly - when containing _- (C _{2 4} alkylene) glycol (c ^4), which is preferably a polyethylene glycol. When used in the composition of the present invention,
Their components are preferably at most about 7000 [definition
(vi)], for example having an average molecular weight of 6600 or less, more preferably at most about 2000, such as at most 1600, most preferably at most about 500. Preferably, the components have a viscosity at 50 ° C. or more preferably at ambient temperature of at most about 15000 mPa.s., more preferably at most about 1000 mPa.s., and most preferably at most about 200 mPa.s. [See Definition (iv)].
Polyethylene glycols suitable for use as component (c) are described, for example, in Feedler, "Lexikon der Hilfstoffe", Second Revised and Expanded Edition, (1981) Volume 2, pages 726-731. Those described, in particular PEG products (polyethylene glycol) 200, 300, 400 and 600 and P
EG 1000, 2000, 4000 or 6000, in particular 200, 300 and 400, for example substantially according to the following physical properties:

[Table 1]

When containing ₅ alkylene polyol ethers or esters (c ^5), which is preferably C _{3 - -} [0039] Component (c) is C _{3 5} alkylene triol, in particular glycerol,
Ether or ester. A suitable component (c ⁵ ) is
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 - including transesterification products of ols - or poly.

[0040] Particularly suitable components (c ^5), the mixed C _{3 -} is the glycol fatty acid esters - ₅ alkylene triol / poly - (C _{2 - 4} alkylene) glycol fatty acid esters, especially mixed glycerol / polyethylene - or polypropylene .

Particularly suitable components for use according to the invention
The (c ^5), glycerides, e.g. triglycerides and poly - (C _{2 - 4} alkylene) glycols, such as poly - with ethylene glycol and optionally there is a product obtained by glycerin and Noto transesterification. Their transesterification products are generally poly _- (C ₂ - ₄
Alkylene) glycols such as polyethylene glycol and optionally obtained by alcoholysis of glycerides, such as triglycerides, in the presence of glycerin (i.e., performing transesterification of glycerides to poly-alkylene glycol / glycerin components;
That is, poly-alkylene glycolysis / glycerin decomposition). Generally, the reaction is carried out under an inert atmosphere at elevated temperature with continuous stirring, under the indicated components (glyceride, polyalkylene glycol and optionally glycerin).
The reaction is carried out.

[0042] 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 include, for example, olives, almonds, peanuts,
Coconut, palm, soy and wheat malt oils, and especially
Is _{- (16} fatty acid C _12), natural or hardened oils rich in ester residue.

Preferred polyalkylene glycol materials are polyethylene glycols, especially from about 500 to about 40.
00, for example polyethylene glycols having a molecular weight of about 1000 to about 2000.

That is, a suitable component (c⁵) Is a small amount of free
C₃-₅Alkylenetriol and free poly- (C₂-
₅(Alkylene) glycol, together with the relative amounts which can vary
C at ₃-₅Alkylene triol esters, for example
Mono-, di- and tri-esters and poly (C₂-
₄Alkylene) glycol mono- and di-esters
A mixture consisting of As described earlier in this specification,
A preferred alkylenetriol moiety is glyceryl.
Preferred polyalkylene glycol moieties are especially about 50
Polyethylene glycyl having a molecular weight of 0 to about 4000
And a preferred fatty acid moiety is C₁₀-₂₂Fat
Fatty acid ester residues, especially saturated C₁₀-₂₂Fatty acid esthetic
Residue.

Thus, to put it another way, particularly suitable components (c ⁵ ) are natural or hydrogenated vegetable oils and the transesterification products of polyethylene glycol and optionally glycerin, or glyceryl mono-, di- and tri- and ₂₂ fatty acid esters (optionally e.g. minor amounts of free glycerol and free polyethylene glycol comprises obtaining together) or containing or these components _- C _{10 - 22} fatty acid esters and polyethylene glycyl mono - and di -C 10 Composition.

Preferred vegetable oils, polyethylene glycols or polyethylene glycol moieties and fatty acid moieties for the above definitions are as described above. Particularly suitable components described above for use in the present invention (c ⁵⁾ are known products which are commercially available under the trade name Gerushiru (Gelucir), in particular i) Gerushiru 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) Gelsil 44/14, melting point = about 42-46 ° C. and saponification number =
Vi) Gelsyl 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 =
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 =
Xi) Gelsil 62/05, melting point = about 60-65 ° C. and saponification number =
The product is about 70-90.

The products (i) to (x) all have an acid value = <2. Product (xi) has an acid number = <5. The above products (i
i), (iii) and (vi)-(x) all have an iodine number = <3. Product (i) has an iodine number = ≦ 8. Product (iv)
And (v) have an iodine number = <5. Product (xi) has an iodine number = <10. Component having iodine number = <1
(c ⁵ ) is generally preferred. Obviously, the above mixture of components (c ⁵⁾ may also be used in the compositions of the present invention.

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

Further, when the above-mentioned component (c) is used,
The compositions of this invention are preferably formulated in solid unit dosage forms suitable for oral administration, for example, in hard gelatin or soft capsule form suitable for oral administration [see Definition (iii)]. These unit dosage forms, which are described in more detail below, preferably contain, for example, from 2 to 200 mg of component (a) per unit dose.

When component (c) described above is used, components (a) and (c) are preferably in the range of 1: 0.5 to 50 ppw [(a) :( c)] [see definition (ii)] It is present in the composition of the invention in proportion.
Components (a) and (b) are preferably from 1: 3 to 200 ppw [(a):
(b)].

When using component (c) as described above, the compositions of the present invention are also non-aqueous or substantially non-aqueous.
[See Definition (v)], for example, the water content based on the total weight of the composition is preferably 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:-the components (a) and (b) and the components (c ¹ ) to (c
⁴ ) A pharmaceutical composition according to any one of the above definitions (ii) to (v), comprising a diluent selected from any one of the above or a mixture thereof,-the components (a), (b) and ( c ² ), and the definition (i)
providing the components (a), a pharmaceutical composition comprising (b) and ^{(c 5) - i),} ( pharmaceutical composition according to iii) or (v), and.

The component (c) specifically mentioned above [ie, the definition
The component according to any one of (i) to (iv) or (c ¹ ) to (c
⁵ ) is used in the composition of this invention, components (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 from about 1: 1 to 10, more preferably 1: 1 to 5, most preferably about 1: 1.5 to 2.5,
For example, it is present at a ratio of 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: 3-200, preferably about 1: 3-100, more preferably about 1: 3-50 ppw. More preferably, components (a) and (b) are from about 1: 5 to 20, preferably from about 1: 5 to 10, and most preferably from about 1: 6.0 to 6.0.
5, for example at a ratio of about 1: 6.25 ppw [(a) :( b)].

The composition according to the invention comprises saccharose monolaurate as component (b) and 1,2- as component (c).
When containing propylene glycol, components (a) and (b)
Is preferably present in a ratio of about 1: 6 to 7 ppw [(a) :( b)], and components (a) and (c) are preferably about 1: 1.5 to 2.5.
5, for example at a ratio of about 1: 2 ppw [(a) :( c)].

The composition according to the invention comprising the aforementioned component (c) can be used, for example, for oral, parenteral or topical application, for example for intralesional injection in the treatment of autoimmune conditions of the eye, for example of said conditions or of psoriasis, for example. It can be manufactured in dosage forms suitable for, for example, skin or ophthalmic applications, for example, for application to the surface of the eye.

Preferably, the compositions, whether orally administered or otherwise, will be manufactured in a unit dosage form. Of course, the ingredients present in their unit dosage form
The amount of (a) will vary depending, for example, on the condition to be treated, the intended mode of administration and the effect desired. In general, however, those unit dosage forms will suitably contain from about 2 to about 200 mg of component (a) per unit dose, for example "cyclosporin".

Dosage forms suitable for oral administration include, for example, liquids, granules and the like. However, preferred is
Solid unit dosage forms, such as tablets or encapsulated forms, especially hard or soft gelatin capsules. Their oral unit dosage form is preferably from about 5 to about 20 per unit dose.
0 mg, more preferably about 10 or 20 to about 100 mg,
It contains, for example, 15, 20, 25, 50, 75 or 100 mg of component (a), for example "cyclosporin".

The compositions according to the invention containing the above-mentioned component (c) are characterized in that they have modified release properties, for example after oral administration, for example delayed release of component (a) or release of component (a) over an extended period of time. It has the further advantage of being able to provide a base for a composition that exhibits properties. The 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, for example polymeric or colloidal thickeners, and agents which are swellable in water, for example water-swellable polymers or colloids.

Suitable components (d) are known in the art and include: d ¹ ) Polyacrylate and polyacrylate copolymer resins, such as polyacrylic acid and polyacrylic acid-methacrylic acid resins, such as known products marketed under the trade name Carbopol (Carbopol, Fedlar,
1 , pp. 206-207), especially Carbopol products 934, 940 and 941, and Eudragit (Feedler, supra, 1 , 372-373);
In particular, Eudragit products E, L, S, RL and RS,
The most restrictive are Eudragit products E, L and S.

D ² ) celluloses and cellulose derivatives, such as alkyl celluloses, such as methyl-, ethyl- and propyl-cellulose, hydroxyalkyl-celluloses, such as hydroxypropyl-cellulose and hydroxypropylalkyl-cellulose, such as Hydroxypropyl-methyl-cellulose, acylated celluloses such as cellulose acetate, cellulose acetate phthalate, cellulose acetate succinate and hydroxypropylmethylcellulose phthalate and salts thereof such as sodium carboxymethylcellulose. Examples of such products suitable for use according to the invention are known and include, for example, Klucel and Metcel.
hocel) under the trade name (Feedler,
Supra, 1, reference 521 pages and 2, 601 pp.), In particular Klucel LF, MF, GF and HF and Methocel K1
00, K15M, K100M, E5M, E15, E15
M and E100M products.

D ³ ) Polyvinylpyrrolidones such as poly-N-vinylpyrrolidone and vinylpyrrolidone copolymers such as vinylpyrrolidone-vinyl acetate copolymer. Examples of such compounds which are suitable for use according to the invention are known and are commercially available, for example under the trade name Kollidon (Feedler, supra, 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 their salts, such as sodium alginate.

D ⁵ ) Silicon dioxides, for example hydrophilic silicon dioxide products, such as alkylated (eg methylated) silica gels, in particular the known colloidal silicon dioxide products marketed under the trade name Aerosil [Handbook・
Of Pharmaceutical Excipients '' (Hand
book of Pharmaceutical Excipients), published by the Pharmaceutical Society of Great Britain, pages 253-256], especially Aerosil products 130, 200, 300, 380, O, OX50, T
T600, MOX80, MOX170, LK84 and methylated Aerosil R972.

When component (d) is present, it is preferably present in an amount of about 0.5 to about the total weight of components (a) + (b) + (c) + (d).
It is present in an amount of 50% by weight, more preferably about 1-20% 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 water-insoluble or substantially water-soluble. It is an insoluble polymeric carrier.

Particularly preferred as component (c ⁶ ) are polyvinylpyrrolidones [Feedler, supra, 2 , 748].
-750 pages], especially crosslinked polyvinylpyrrolidones. Examples of such materials suitable for use in this invention are known, Kollidon [Fiedler, supra, 1, 5
See page 27], Kollisept [Feedler,
Supra, 2 , pp. 719-720], and Povidon.
e) and Crospovidone (Feedler, supra, see 2 , p. 751).

Particularly suitable components (c ⁶ ) are at least about 1
Polyvinylpyrrolidones having a molecular weight of 0000, more preferably at least about 20,000 or 25,000, for example about 40,000 or more.
Crosslinked polyvinylpyrrolidones are of particular interest. Examples of specific products suitable for use in the present invention as (c ⁶ ) include Plasdone XL, Plasdone XL10 and Crospovidone.

When the compositions according to the invention comprise component (c ⁶ ), they are preferably also (d) a water-swellable or water-soluble component, such as cellulose or a cellulose derivative as defined in (d ² ) above. including.

Still other examples of those materials of particular interest for the compositions of this invention containing component (c ⁶ ) include Avicel [Feedler, supra, 1 , 160-16.
See page 1], Elcema [Feedler, supra,
1 , 326] and Pharmacoat (see Feeder, supra, at 2 , page 707), such as the Avicel PH101 and PH102, Elsema and Pharmacoat 603 products.

In the case of the composition according to the invention comprising component (c ⁶ ), component (a) is in solid solution, for example in component (b) which is a complete or substantially complete solid micellar solution, molecule or micellar dispersion. Exists. [In practice, component (b) is not "solid" in its most strict sense because it often exhibits at least some fluidity, for example at ambient or slightly elevated temperature. Accordingly, the term "solid solution" as used in this specification, including the claims,
For example, it should be interpreted as including 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, the component (c ⁶ ) is generally used in the composition of the present invention [(a)
+ (B)] as a collapsible matrix. Component (d) generally functions as a disintegration aid, for example, upon contact with the contents of the gastrointestinal tract.

The composition according to 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-
2 2} alkylsulfonic acid alkali metal or alkaline earth metal salts, such as sodium, calcium or magnesium salts. Examples of those materials suitable for use in the present invention are sodium lauryl sulfate and magnesium stearate [Feedler, supra;
2 , p. 584].

When the composition of the present invention comprises component (c ⁶ ), components (a) and (b) are suitably present in an amount of about 1: 2 to 20, preferably about 1: 2.5 to 10, most preferably about 1: 2.5 to 10, Preferably about 1: 3 to
It exists at a ratio of 8 [(a) + (b)].

Component (c ⁶ ) is suitably at least 10%, more preferably at least 15%, more preferably at least 20% by weight relative to the total weight of the composition.
Is present in the composition of the invention. Preferably, the ingredients
(c ⁶ ) is 10 to 60% by weight based on the total weight of the composition,
More preferably 15 to 50% by weight, for example about 20 to 4%
0% by weight, for example about 25, 30 or 35% by weight, is present in the composition according to the invention.

When component (d) is present, components (d) and (c)
⁶ ) is suitably about 1: 0.5 to 4, more preferably about 1: 1 to 3, most preferably about 1: 1.5 to 2.5, for example about 1: 2 or about 1: 2. It is present at a rate of .5 ppw [(d) :( c ⁶ )].

When component (e) is present, components (e) and (c)
⁶) Is suitably about 1: 5 to 25, more preferably about
1: 5-20, most preferably about 1: 7-15 ppw ratio
[(e) :( c ⁶)]. The composition of the present invention comprises three components (c
⁶), (D) and (e), they all comprise the composition
Preferably about 25-75%, more preferably
Or about 30-65%, most preferably about 40-65%
Present together in the amount of Component ratio [(a) + (b)]: [(c) + (d)
+ (E)] is preferably 1: 0.25 to 7.5, more preferably
1: 0.5-5, most preferably 1: 0.5-2, e.g.
If it is about 1: 0.8, 1: 1.2 or 1: 1.3 ppw
You.

The composition according to the invention containing component (c ⁶ ) can be manufactured in any dosage form suitable, for example, for oral, parenteral or topical application. Preferably, the compositions according to the present invention, whether orally or otherwise administered,
Manufactured in unit dosage form.

Of course, the amount of component (a) present in these unit dosage forms varies depending, for example, on the condition to be treated, the intended mode of administration and the effect desired. However, in general, they are preferably about 2 to about 2 doses per unit dose.
It contains about 200 mg of component (a), for example "cyclosporine".

Dosage forms suitable for oral administration include granules and the like. However, preference is given to solid unit dose forms, for example tablets or capsules. Their oral unit dosage form is preferably about 5 per unit dose.
To about 200 mg, more preferably about 10 or 20 to about 1
00 mg, for example 15, 20, 25, 50, 75 or 1
Contains 00 mg of component (a), for example "cyclosporin".

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

Paraffin hydrocarbons suitable for use as component (c ⁷ ) are liquid and semi-solid paraffins and mixtures thereof, ie sub-liquid and super-liquid paraffins [Feedler, supra, 2 , 690-6].
See page 91]. In order to facilitate formulation, the component (c ⁷ )
Preferably it is constituted or consists essentially of fluid or semi-solid paraffins, ie superfluid or subfluid paraffin or mixtures thereof. However, if, for example, it is desired to produce a composition with slower active ingredient release characteristics, this can be achieved by adding more 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]. I do. In this case, components (a) and ^{(c 7)} is suitably from about 1: 6 to 200, more preferably from about 1: 6-10
0, most preferably 1: 6-20, for example about 1: 8 ppw
It exists in the ratio of [(a) :( c)].

If 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 to 0.1 ppw. In this case, components (a) and (c
⁷ ) is suitably 1: 6-200, more preferably 1:
6-100, most preferably 1: 8-20, for example about 1:
It is present at a rate of 10 ppw [(a) :( c ⁷ )].

Organic silicon oxide polymers suitable for use as component (c ⁷ ) include, in particular, fluids, ie of the formula —R ₂ Si—
(Wherein each R is a monovalent organic radical, for example C _{1 - 4} alkyl, in particular methyl or phenyl) O- include liquid and semi-solid polymeric material having a structural unit represented by the. Especially preferred are organosiloxane polymer having a viscosity of about from .65 to 10 ⁵ cP, especially about 10 or 50 to 500 or 1000 cP.

To facilitate formulation, component (c ⁷ )
Suitably a liquid organosiloxane polymer, such as a poly-methyl siloxane polymer, such as any of a variety of known silicone oils, such as silicone oil 550, DC200, SF-
1066 and SF-1091 [Feedler, supra,
2 , page 826]. If the composition according to the invention comprises only a liquid organosiloxane polymer, the components
(a) and ^{(c 7)} is suitably from about 1: 6 to 200, more preferably from about 1: 6 to 100, and most preferably from 1: 6 to 2
0, for example at a ratio of about 1: 8 ppw [(a) :( c ⁷ )].

[0085] For example, the composition having a slower active ingredient release characteristics, either semi-solid organosiloxane polymer as component (c ^7), for example, various known silicon paste, such as silicon paste A [Fiedler, supra, 2 ,
826] or by adding them to, for example, the other aforementioned organosilicon oxide polymers. In the latter case, the liquid present in the composition of the invention:
The proportion of semisolid organosilicon polymer is preferably about 1: 0.5.
~ 1. In this case, the ratio of component (a) :( c ⁷ ) is
Suitably about 1: 6-100, preferably about 1: 6-20 pp
w [(a): (c ⁷ )].

Obviously, mixtures of the aforementioned components (c ⁷ ) can also be used in the composition according to 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
-10, most preferably about 1: 6.0-6.5, such as about 1: 6.25 ppw [(a) :( b)].

The component (c)⁷) Of the composition of the present invention
If component (a) is completely or substantially completely molecular or
In the form of micellar dispersions, such as solid solutions or solid micellar solutions
Present in component (b) in the form [provided that the term "solid solution"
Is the component (c ⁶Same broad meaning as)
Used in]. (a) and (b)
The solution preferably comprises component (c)⁷), For example, component (c⁷)all
It is dispersed in the body in the form of particles, for example fine particles.

A composition according to the invention comprising component (c ⁷ ) may be used, for example, for the treatment of autoimmune conditions of the eye, for example the aforementioned conditions, or for intralesional injection, for example for the treatment of psoriasis, for example orally, parenterally or It may be manufactured in a dosage form suitable for topical application, for example, skin or ophthalmic application, for example, to the surface of the eye. Preferably, they are prepared in unit dosage form, whether orally or by other modes of administration.

The amount of component (a) present in these unit dosage forms will, of course, vary with, for example, the condition to be treated, the intended mode of administration and the effect desired. However,
Generally, they contain suitably from about 2 to about 200 mg of component (a) per unit dose, for example "cyclosporin".

[0090] Dosage forms suitable for oral administration include liquids, granules and the like. However, preference is given to solid unit dose forms, for example tablets or encapsulated forms, especially hard or soft gelatin capsules. Their oral unit dosage form is suitably from about 5 to about 20 per unit dose.
0 mg, more preferably about 10 or 20 to about 100 mg,
It contains, for example, 15, 20, 25, 50, 75 or 100 mg of component (a), for example "cyclosporin".

The compositions according to the invention which comprise component (c ⁷ ) have improved release characteristics, for example after oral administration, such as delayed release of component (a) or release of component (a) over a longer period of time. Another advantage is that a base for a composition exhibiting such properties can be provided. These compositions can be prepared as described above by entrapping the solid or semi-solid component (c ⁷ ) in an appropriate amount. Alternatively, they can be prepared by including an 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 capable of swelling in water, such as water-swellable polymers or colloids, such as those described above ( d ¹⁾ includes any ~ (d ⁵⁾ as defined in claim material.

When component (d) is present, it is preferably present in an amount of about 0.5% based on the total weight of components (a) + (b) + (c ⁷ ) + (d).
It is present in an amount of 5-30%, more preferably about 1-20%, most preferably about 1-10%.

Component (d ⁵ ) is particularly suitable for use in a composition according to the invention which comprises 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 for a composition comprising other components (c), or preferably That is the state.

The composition according to the invention comprises selected components
independent of (c) [eg, whether component (c) comprises any ^{one of the} aforementioned components (c ¹ ) to (c ⁷ ) or a mixture thereof] and additional additives such as 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, in particular to prevent hydrolysis of component (b) or of component (a) during the processing step or during storage. Or it contains a buffer. Those stabilizers are
Acidic stabilizers, such as citric acid, acetic acid, tartaric acid or fumaric acid, and basic stabilizers, such as potassium hydrogen phosphate;
It may include glycine, lysine, arginine or tris (hydroxymethyl) aminomethane.

The 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, for example 6-7. . These stabilizers are generally used, for example when citric acid or acetic acid is used, in amounts of 5
It is present in an amount of less than or equal to 10% by weight. Preference is given to compositions according to the invention having a pH in the above range, in particular those in which component (a) is "cyclosporin".

The compositions according to the invention are also preferably surfactants containing no polyoxyalkylene, such as dioctyl succinate, dioctyl-sulfo-succinate,
[2-Ethylhexyl] -succinate, sodium lauryl sulfate or phospholipids, including lecithins. If the surfactant is present, this is preferably component (b)
5 to 50, more preferably 10 to 5, based on the weight of
It is present in an amount of 0, for example 10 to 25%.

In the case of the composition of the present invention containing component (a) as a solid solution in component (b), for example, when component (c) is component (c ⁶ ) or (c ⁷ ), the stabilizer described above is used. , Buffers and / or surfactants are preferably incorporated into the solid solution phase. Those materials may also be included in component (c) and the like.

The compositions according to the invention are also preferably free or substantially free of ethanol, independently of the component (c) chosen, for example, by 5.0%, based on the total weight of the composition. Less than 2.5%, more preferably less than 2.5%, for example 0-1.0% ethanol.

In addition to the above, the present invention also relates to a process for producing the above-mentioned pharmaceutical composition, wherein said components (a), (b) and (c) are optionally replaced with component (d) and / or other components. Ingredients,
For example, by intimately mixing or formulating with the aforementioned stabilizers, buffers or surfactants, if necessary, for example by tableting, filling into gelatin capsules or other suitable means.
There is provided a method comprising formulating the resulting composition in a unit dosage form, eg, a unit dosage form for oral administration.

The component (c) is a solvent for the components (a) and (b), or the component (c ¹ ), (c ² ), (c ³ ), (c
⁴⁾ or containing (c ^5), components (a), (b) and (c)
The components are suitably heated, for example at a temperature not exceeding 50 ° C. to 150 ° C., preferably not exceeding 70 or 75 ° C.
The above processes are combined by dissolving (a) and (b) together in component (c). Next, the mixture thus obtained can be further mixed with the component (d) or the like, for example, by intimate mixing according to a technique known in the art. Filling, for example, into hard or soft gelatin capsules is preferably carried out at an elevated temperature, for example at 50 ° C. or lower, to achieve the fluidity of the composition, for example, in warm air.

Compositions according to the invention comprising component (a) as a solid solution in component (b), such as component (c ⁶ ) or (c)
^In the case of a composition comprising ⁷ ), the method preferably comprises firstly (b)
Producing a solid solution containing medium (a), and then intimately mixing or blending the resulting solid solution with the remaining components (c) and, if desired, (d) and the like.

The solid solution containing the component (a) in the component (b) may be prepared by solidifying a melt containing the component (a) dissolved in the component (b) or by solidifying the component (a) according to a known technique in the art. And (b) by removing 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, for example ethanol. Stabilizers, buffers and / or surfactants are preferably incorporated in the dissolution step.

Next, the solid solution thus obtained is preferably distributed, for example, in the component (c), for example, in the form of fine particles, and optionally the components (d) and (e).
Mix with etc.

Ethanol may be used for the purpose of preparing the composition of the invention, for example in the preparation of said solid solution, but it is preferably removed, for example by evaporation before completion of the final dosage form, so that The aforementioned ethanol-free or substantially ethanol-free product is obtained.

[0107]

The present invention will be described below with reference to 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 1
2.3, Lauryl ester residue purity = at least 95
%, MP = about 35 ° C., decomposes at about 235 ° C., 0.1% by weight
Surface tension of aqueous solution = about 72.0 dyn / cm at 25 ° C.

[0108]

[0109]

[0110]

[0111]

[0112]

[0113]

[0114]

[0115]

[0116]

[0117]

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 a similar 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)
Are suspended in (a) to (c).

The final encapsulated capsule is filled by filling the resulting composition into a hard gelatin capsule, size 1 (Examples 1-4 and 9) or size 0 (Examples 5-7 and 10) while warming. The product is obtained. Each capsule contains 50 mg of cyclosporine (eg, "cyclosporine") and is suitable for administration in preventing transplant rejection or treating autoimmune disease, for example, 1-5 capsules daily.

[0120]

[0121]

[0122]

The above compositions 11 to 13 preferably each further comprise 25 mg of (f) tartaric acid and / or 50 mg of (g) dioctyl succinate, preferably both, the final weight being 1000 mg, 1 for composition 12
055 mg and 6180 mg for composition 13.

Compositions 11 to 13 are prepared in the following manner. The 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 [(f) and
Add these when using (g)]. The solid solution containing [(a) + (b)] is pulverized to a fine powder, and uniformly mixed into [(c)-(g)], and the resulting uniform mass is 100, 50 or 25, respectively.
mg (a) and is compressed into tablets suitable for administration in the prevention of transplant rejection or in the treatment of autoimmune diseases, for example, administration of 1 to 5 tablets daily.

[0125]

[0126]

The 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 hard gelatin capsule,
Filling to size 0 gives the final product encapsulated. Each capsule contains 50 mg of cyclosporine (eg, "cyclosporine") and is suitable for administration in preventing transplant rejection or treating autoimmune disease, for example, 1-5 capsules daily.

[0128]

[0129]

Compositions 16 and 17 are also the same as those in the above 14 and 1
It is manufactured in the same manner as in No. 5. In the case of composition 16, first
Combine (c) and (d) by melting and tightly stir together. Next, the solid solution containing [(a) + (b)] was added to [(c) +
(d)]. In the case of the composition 17, (d) is changed to [(a) + (b)].
Together with (c).

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

The utility of the compositions according to the invention can be shown, for example, in animal or clinical trials performed as follows. Bioavailability tests on compositions of the 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 eight beagle dogs (male, about 11-13 kg) is used. 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 Na
20 ml of a 0.9% solution of Cl are administered. Three hours after administration of the test composition, the animals are allowed free access to food and water.

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

The blood sample is analyzed by RIA. The area under the blood drug concentration versus time curve is calculated according to the trapezoidal rule. The analysis of the amount of variance was performed using AUC (area under the curve),
And Tmax (time of maximum value).

C) Results Average AUC (ng · h / ml-
¹ ) and Cmax (ng / ml- ¹ ) values are shown in the table below along with the calculated variability (CV) in the response between test animals receiving the same composition.

[0137]

As is evident from the table above, the compositions according to the invention exhibit a high bioavailability (AUC and Cmax) associated with a relatively low variability in the response of interest with respect to both AUC and Cmax.

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

Clinical Trials The advantageous properties of the compositions of the invention for oral administration can also be demonstrated, for example, in clinical trials performed as follows. The test subjects are adult volunteers, such as professionally educated men aged 30 to 55 years. The test group preferably consists of 12 subjects.

The following inclusion / exclusion criteria apply. Inclusion: Normal screening ECG, normotensive and heart rate, body weight = 50-95 kg. Exclusions: clinically significant interventional medical conditions that may conflict with drug absorption, distribution, metabolism, elimination or safety, signs of clinically significant disease 2 weeks prior to study, abnormal clinically significant laboratory values Or electrocardiogram, need for concomitant medical care throughout the course of the study, administration of a drug 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, history of drug or alcohol dependence, blood loss of 500 ml or more in the last 3 months, drug side effects or hypersensitivity, history of allergy requiring drug treatment, hepatitis B / HIV positive .

Before and after the test, a complete physical examination and EC
Perform G. 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, S
GOT, SGPT, -GT, alkaline phosphatase, total bilirubin, α-amylase. Urine-pH, microalbumin, glucose, erythrocytes, ketone bodies, sediment.

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

Dosing is performed in the morning after a 10-hour overnight fast (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 have a standard lunch.

One hour before administration and 0.25, 0.2
5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4, 4.5,
Blood samples (2 ml) are taken after 5, 6, 9, 12, 14, 24, 28 and 32 hours. To determine creatinine, a 2 ml blood sample was administered immediately prior to administration and at 12, 2
Collect after 4 and 48 hours. A sample for cyclosporin measurement was transferred to two EDTA-coated polystyrene tubes at each time point.
(1 ml each) and gently agitated followed by quick freezing at -20 ° C. R by specific and / or non-specific MAB test
Cyclosporin in whole blood is measured using IA. Detection limit in both cases = about 10 ng / ml.

In the tests carried out according to the above protocol, for example, the composition of Example 1 in the form of hard gelatin capsules was prepared by using as standard the drinking solution of “cyclosporin” (“cyclosporin” = 50 mg, labrafil = 150 mg, ethanol =
Established AUC (0-32 hours) and Cmax when compared to 50 mg, corn oil = 213 mg, final weight of contents in soft gelatin capsule form = 463 mg / dose)
A significant increase in the level of bioavailability is recorded for the composition of Example 1 as compared to the standard, as reflected in both values. In addition, comparing the change in whole blood "cyclosporin" concentration over time after a single dose of the test composition (150 mg "cyclosporin" dose) (measured by specific monoclonal RIA), all subjects receiving the standard composition It is demonstrated that the variability of the response between all the subjects administered the composition according to Example 1 is significantly reduced compared to the case of

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

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61K 47/46 A61P 7/06 A61P 7/06 17/00 17/00 19/02 19/02 21/00 21/00 29/00 29/00 101 101 37/06 37/06 A61K 37/00 (31) Priority claim number 8903663.6 (32) Priority date February 17, 2001 (February 17, 1989) (33) Priority country United Kingdom (GB) F-term (reference) 4C076 AA53 BB01 CC07 DD34 EE13 EE23 EE27 EE30 4C084 AA03 BA01 BA07 BA18 BA24 CA04 MA05 MA37 MA52 ZA55 ZA89 ZA94 ZA96 ZB08 ZB11 ZB15

Claims (34)

[Claims] 1. A pharmaceutical composition comprising (a) cyclosporin as an active ingredient, (b) a fatty acid saccharide monoester, and (c) a diluent or carrier, wherein (i) component (c) is a component (c) solvent for both a) and (b), wherein components (a) and (b) are each independently components at ambient temperature
(c) has a solubility of at least 10%, or (ii) component (c) is a solvent for both components (a) and (b), and components (a) and (c) are Medium 1: 0.5-50
ppw [(a) :( c)] or (iii) component (c) is a solvent for both components (a) and (b) and the composition is suitable for oral administration Or (iv) component (c) having an average molecular weight of at most 7000 or a viscosity at 50 ° C. ambient temperature of at most 15000 mPa.s. C 2 _{- 4} alkylene) - or glycols, or C _{3 - 5} whether containing alkylene polyol ethers or esters, or (v) said composition is non-aqueous or substantially non-aqueous, or ( vi) Component (c) comprises a solid polymer carrier, an organosilicon oxide polymer or per- or sub-sub liquid paraffin, and component (a) is a solid solution in (b) in the composition. The composition that is present. Wherein (a) as an active ingredient cyclosporin, (b) fatty acid saccharide monoester, and ^(c) (c ¹⁾ Ethanol (c _²⁾ C ² _{- 4} alkylene glycol (c _³⁾ C ³ _{- 5} alkylene polyols (c ⁴⁾ poly - _{(C 2} - ₄ alkylene) a glycols and pharmaceutical compositions containing diluents selected from the group consisting of mixtures thereof, (ii) components (a) and (c ) Is 1: 0.5 to 50 in the composition.
ppw [(a) :( c)], or (iii) the composition is formulated in a solid unit dosage form suitable for oral administration, or (iv) the component ( c) comprises a component (c ⁴ ) having an average molecular weight of at most 7000 or a viscosity at 50 ° C. of at most 15000 mPa.s. or (v) said composition is non-aqueous or substantially A composition that is non-aqueous. 3. Component (c) comprises (c ² ) 1,2-propylene glycol (c ³ ) glycerin and (c ⁴ ) an average molecular weight of at most 7000 or at most 1
The composition according to claim 2, wherein the composition is selected from the group consisting of polyethylene glycols having a viscosity at 50 ° C of 5000 mPa.s. 4. A pharmaceutical composition comprising (a) cyclosporin as an active ingredient, (b) a fatty acid saccharide monoester, and (c) 1,2-propylene glycol, wherein (ii) component (a) ^{(c 2)} is, the composition 1: 0.5-5
(Iii) is present in a ratio of 0 ppw [(a) :( c ² )], or (iii) said composition is formulated in a solid unit dosage form suitable for oral administration; A composition wherein the composition is non-aqueous or substantially non-aqueous. 5. (a) cyclosporin as an active ingredient, (b) fatty acid saccharide monoester, and (c _⁵⁾ C _{3 -} ⁵ pharmaceutical compositions containing alkylene polyol ethers or esters. 6. The composition according to claim ^{5, wherein} component (c ⁵ ) comprises a transesterification product of a natural or hydrogenated vegetable oil and polyethylene glycol. 7. The composition according to claim 6, wherein component (c ⁵ ) comprises a transesterification product of a natural or hydrogenated vegetable oil and a polyethylene glycol having a molecular weight of from 500 to 4000. 8. Component (c ⁵ ) is a natural or hydrogenated vegetable oil,
The composition according to claim 6 or 7, comprising a transesterification product of polyethylene glycol and glycerin. 9. Component (a) and (c ⁵ ) are from 1: 0.5 to 50
9. The composition according to claim 5, wherein the composition is present in a ppw ratio. 10. Component (a) and (c) or (c)²) (Claim
4) or (c ⁵) (In claims 5 to 9) is 1: 1
-10 ppw [(a): (c) / (c²) / (C⁵)]
The composition according to claim 1. 11. The composition according to claim 10, wherein the ratio is from 1: 1.5 to 2.5 ppw. 12. Components (a) and (b) are in a ratio of 1: 3-200 p.
The composition according to any one of the preceding claims, wherein the composition is present in the ratio pw [(a) :( b)]. 13. The composition according to claim 12, wherein the proportion is between 1: 5 and 20 ppw. 14. The composition according to claim 13, wherein the ratio is between 1: 6 and 6.5 ppw. 15. A pharmaceutical composition comprising (a) cyclosporin as an active ingredient in a solid solution, (b) a fatty acid saccharide monoester, and (c ⁶ ) a solid polymer carrier. 16. The composition according to claim 15, wherein component (c ⁶ ) comprises polyvinylpyrrolidone. 17. Component (a) and (b) are present in an amount of 1: 2 to 20 ppw
17. The composition according to claim 15 or 16, wherein the composition is present in the ratio of [(a) :( b)]. 18. The method according to claim 1, wherein the ratio is 1: 3 to 8 ppw.
A composition according to claim 7. 19. The composition of claim 15, wherein component (c ⁶ ) is present in an amount of at least 10% by weight, based on the total weight of the composition.
The composition according to any one of claims 18 to 18. 20. The composition according to claim 19, wherein component (c ⁶ ) is present in an amount of 15 to 50% by weight, based on the total weight of the composition. 21. The composition according to any one of claims 15 to 20, further comprising (d) a water-swellable component. 22. Components (d) and (c ⁶ ) are in the range of 1: 0.5-4
ppw present in proportions ^{[(d) :( c 6)} ], 21. A composition according. 23. In a unit dose form, 2 per unit dose
24. The composition according to any one of claims 1 to 23, comprising from -200 mg of component (a). 24. About 10 or 20 per unit dose
24. The composition according to claim 23, comprising about 100 mg of component (a). 25. A pharmaceutical composition comprising (a) cyclosporin as an active ingredient, (b) a fatty acid saccharide monoester, and (c ² ) 1,2-propylene glycol, wherein 1 unit is in a unit dosage form. A composition comprising about 20 to about 100 mg of component (a) per dose, wherein components (a) and (b) are present in the composition in a ratio of 1: 3 to 2
A composition wherein the components (a) and (c) are present in the composition at a ratio of 1: 0.5 to 50 ppw, being present at a ratio of 00 ppw [(a) :( b)]. 26. Components (a) and (b) are present at a ratio of 1: 5 to 10 ppw, and components (a) and (c) are present at a ratio of 1: 1.5 to 2.5 ppw.
26. The composition of claim 25, wherein the composition is present in a proportion of 27. The composition according to claim 1, which is in an oral dosage form encapsulated in soft or hard gelatin. 28. The composition according to claim 1, further comprising a stabilizer or a buffer. 29. The buffer of claim 28, buffered to a pH of 3-8.
A composition as described. 30. Component (a) is “cyclosporine” or
30. The composition according to any one of claims 1 to 29, which is [Nva] ^2- "cyclosporin". 31. The composition according to claim 1, wherein component (b) comprises a water-soluble fatty acid saccharide monoester. 32. A component (b), C 6 _{- 18} fatty acid di- - or tri - containing saccharide monoester, 31. A composition according. 33. The composition according to claim 32, wherein component (b) comprises raffinose or sucrose monolaurate. 34. The composition of any one of claims 1-33, substantially as described with respect to any one of the Examples below.