JP3484190B2 - New cyclosporin preparation - Google Patents

Description

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

[Prior Art] Cyclosporins are a group of cyclic poly-N-methylated endecapeptides having a unique structure, which usually have pharmacological properties, particularly immunosuppressive, anti-inflammatory and / or antiparasitic activity. Includes. The first isolated cyclosporins were the natural fungal metabolite "Ciclosporin" or Cyclosporine, also known as Cyclosporin A, marketed under the trade name SANDIMMUN or SANDIMMUNE. .
"Cyclosporine" is cyclosporine represented by formula (A).

[In the formula, -MeBmt- is the formula (B). (In the formula, -xy- is -CH = CH- (trans)) N-methyl- (4R) -4-but-2E-ene-
Represents a 1-yl-4-methyl- (L) threonyl residue] As this type of matrix, "cyclosporine" has received the most attention so far. The main areas of clinical research on cyclosporine are immunosuppressants, especially organ transplants,
For example, it relates to its application to heart, lung, cardiopulmonary, liver, kidney, pancreas, bone marrow, skin and corneal transplants and especially recipients of atypical organ transplants. "Cyclosporine" has received significant results and recognition in this area.

At the same time, the applicability of "cyclosporin" to various autoimmune diseases and inflammatory conditions, in particular inflammatory conditions due to etiology involving the autoimmune component, such as arthritis (eg rheumatoid arthritis, chronic progressive arthritis and osteoarthritis) and rheumatism disease, is Very strong, reports and results in vitro, in animal models and in clinical trials are well documented in the literature. Specific autoimmune diseases for which “cyclosporin” therapy has been proposed or applied include autoimmune blood diseases (eg, hemolytic anemia, non-renewable anemia, congenital aplastic anemia and idiopathic thrombocytopenia). , Systemic lupus erythematosus, polychondritis, scleroderma, Wegenel's granulomatosis, dermatomyositis, chronic active hepatitis,
Myasthenia gravis, psoriasis, Steven-Johnson syndrome, idiopathic sprue, autoimmune inflammatory bowel disease (eg,
Ulcerative colitis and Crohn's disease), endocrine eye disease, Graves' disease, sarcoidosis, multiple sclerosis,
Primary biliary cirrhosis, juvenile diabetes (diabetes mellitus I
Type), uveitis (anterior and posterior), keratoconjunctivitis sicca and keratoconjunctivitis sicca, interstitial pulmonary fibrosis, psoriatic arthritis and glomerulonephritis (eg, idiopathic nephrotic syndrome or nephropathy including micropathic nephropathy). With or without the syndrome).

Another area of research is its potential application as antiparasitics, especially as antiprotozoal agents, and has potential uses, including the treatment of malaria, coccidioidomycosis and schistosomiasis, and more recently, for example other anti-neoplastic agents. It has also been suggested for use in treating cancer as a drug that removes or eliminates resistance to cytostatic therapy.

A wide range of natural cyclosporins have been isolated and identified since the initial discovery of cyclosporins, and many additional non-natural cyclosporins have been produced by the application of whole or semi-synthetic means or modified culture techniques. That is, there are many kinds of cyclosporins included, for example, natural cyclosporins A to Z [reference, travers, etc., 1, “Helvetica Cimica Actor] (Helv.
m.Acta.) 60 , 1247-1255 (1977), travers, etc. 2,
"Helvetica Shimika Actor" (Helv.Chim.Act
a.) 65 , No. 162, 1655-1667 (1982), Corbel et al., “European Journal of Applied.
Microbiology and Biotechnology "
(Europ. J. Applied Microbiology and Biotechnology)
14 , 273-240 (1982), and von Bartberg et al., "Progress in Allergy" (Progress in
Allergy), 38 , 28-45 (1986)], and various non-natural cyclosporin derivatives and artificial or synthetic cyclosporins, such as the so-called dihydro-cyclosporins [wherein the -xy-moiety of the -MeBmt- residue ( by saturating the formula B), -x-y - = - CH 2 -C
H ₂ — is obtained], derivatized cyclosporins (eg, when another substituent is introduced at the α-carbon atom of the sarcosyl residue at position 3 of the cyclosporine molecule), —MeBmt-residue in isomeric form. Existing cyclosporins (eg, -MeBmt-
(If the configuration between the 6'and 7'positions of the residue is cis rather than trans), and the use of the total synthetic cyclosporine production method developed, for example, by Wenger, allows the mutated amino acid to be placed at a specific position in the peptide sequence. Cyclosporins incorporated [eg Traver 1, Traver 2
And Corbell, supra, U.S. Pat. No. 4,108,985.
No. 4210581 and No. 4220641, European Patent Publication No. 0034567, No. 0056782 and No. 0296122.
No., International Patent Publication No. WO86 / 02080, Wenger 1, “Transplantation Proceedings” (Tran
sp.Proc.) 15 , Addendum 1: 2230 (1983), Wenger 2,
"Angewante Chemie International Edition in English" (Angew.Chem.Int.E
d.), 24 , 77 (1985) and Wenger 3, "Progress in the Chemistry of Organic Natural Products" (Progress in the Chemistry).
of Organic Natural Products), 50 , 123 (1986)].

That is, the types included in cyclosporins include, for example, [Thr] ² −, [Val] ² −, [Nva] ² − and [Nva] ² [Nva] ⁵ − “cyclosporin” (cyclosporin C and D, respectively). , G and M), [3′-O-acyl-MeBmt] ^1- “cyclosporin” (also known as cyclosporin A acetate), dihydro- [MeBmt] ^1- [Val]. ^2- "cyclosporin" (also known as dihydro-cyclosporin D), 3'-desoxy-3'-oxo- [MeBmt] ¹
- ^{[Val] 2} - and - ^{[Nva] 2} - "Cyclosporin", [(D) ^{fluoromethyl-Sar] 3} - ^{"Cyclosporin", [(D) Ser] 8} - "cyclosporin", [M
eIle] ¹¹ - ^{"cyclosporine", [(D) MeVal] 11} -
"Cyclosporin" (also known as Cyclosporin H), [MeAla] ^6- "Cyclosporin",
[(D) Pro] ^3- "Cyclosporine" and the like.

[According to the current conventional nomenclature for cyclosporins, they are defined on the basis of the structure of "cyclosporin" (ie, cyclosporin A). This shows the amino acid residues that are different (existing) from the amino acid residues that are present in "cyclosporin" first (eg,
"[(D) Pro] ³ )" is the problem cyclosporine
(Indicating that it has a-(D) Pro- rather than a -Sar-residue at position 3), then applying the term "cyclosporin" to the remaining residues corresponding to the residues present in "cyclosporin". This is done by showing the characteristics. The individual residues are numbered starting from the residue at position 1 -MeBmt-, -dihydro-MeBmt- or equivalent residues thereof. ] Furthermore, the vast majority of these cyclosporins are
There have been many proposals in the literature for their medicinal or even specific utility comparable to that of "cyclosporine", for example, they exhibit an activity of counteracting tumor resistance particularly to cytostatic therapy, and their applicability as therapeutic agents. There is.

Although "cyclosporin" has made a tremendous contribution to the treatment of organ transplantation and autoimmune diseases in particular, it presents difficulties when providing a more effective and convenient means of administration, and undesirable side effects, especially nephrotoxic reactions. The reported occurrence of C. 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 have hitherto been
It was mainly based on the use of ethanol and oils or similar excipients as carrier medium. That is, the commercially available "Cyclosporin" drinking solution uses ethanol and olive oil as carrier media with Labrafil® as a surfactant (see, eg, US Pat. No. 4,388,307). However, the use of drinking solutions and similar compositions that have been proposed in the art
There are various difficulties.

First, the need to use oils or oil-based carriers can add an unpleasant taste to the formulation, or otherwise deteriorate the mouthfeel, especially for long-term therapeutic purposes. These effects can be masked by formulating in gelatin capsule form. However, in order to maintain cyclosporine in solution, the ethanol content must be kept high. For example, when opened, precipitation of cyclosporine appears as a result of evaporation of ethanol, eg from capsules or other forms. Due to this particular problem, it is necessary to package the product enclosed in an airtight compartment, for example an airtight blister or an aluminum foil blister-package, when formulating those compositions in the form of gelatine soft capsules, for example. As a result, the product is bulky and expensive to manufacture. The storage properties of the above formulations are far from ideal.

Also, the bioavailability levels achieved with the existing oral cyclosporine dose system are low and exhibit wide variation between individuals, individual patient types and even in single individuals at different times during the course of treatment. That is, reports in the literature indicate that the currently available therapy with the commercially available "Cyclosporine" drinking solution only resulted in an average absolute bioavailability of only about 30%, and between individual groups, for example liver ( Relatively low bioavailability) and bone marrow (relatively high bioavailability) exhibit significant variability between transplant recipients. The range of variability in bioavailability between subjects may be as low as 1 or a few percent, depending on the patient, and 90
It has been reported that it may reach up to% or even higher. And, as already mentioned, significant changes over time in bioavailability for individuals are frequently observed.

To achieve effective immunosuppressive therapy, cyclosporine blood or serum levels must be maintained within certain limits. In this case, the required range depends on the particular condition being treated, for example, whether the treatment is intended to prevent transplant rejection or control autoimmune disease, or another immunosuppressive therapy is cyclosporine. It may vary depending on whether or not it is being used concurrently with therapy. Due to the wide variation in the bioavailability levels achieved by conventional dosage forms, the daily doses required to achieve the required serum levels 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, which is generally done using RIA or equivalent immunoassay techniques, such as those based on monoclonal antibodies, must be done in an orderly fashion. This is necessarily time consuming and inconvenient, and substantially adds to the total cost of treatment.

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

Various proposals have been suggested in the art to overcome these problems, including both solid and liquid oral dosage forms. That is, Japanese patent application by Takada et al.
No. 60-71682 (Japanese Patent Laid-Open No. 61-280435) shows application of means for increasing lymph node delivery of cyclosporins, specifically by administering in combination with a surfactant. A general list of surfactants that can be used is saccharose (sucrose) fatty acid esters such as sucrose oleate, palmitate or stearate, as well as other fatty acid esters, especially sorbitan fatty acid esters such as sorbitan oleate, palmitate. Or a stearate is included. Although the use of both mono- and poly-esters has been shown, mono- or di-esters have been proposed as generally preferred. Other surfactants listed include the known products marketed under the trade names of polyoxyethyl hydrogenated vegetable oils, such as Cremophor RH and Nikkor HCO60, which are obviously the sucrose.
It has been shown to be preferred over ester surfactants.

In Example 3 of the above-mentioned Japanese application, as a surface-active ingredient,
It describes how to obtain an aqueous formulation containing a sucrose fatty acid ester identified as F160. This formulation is 1m
H containing saccharose ester of "cyclosporin" and 2mg of 3.5mg in ₂ O. Sonication at 100 W for 5 minutes is required to achieve dispersion of "cyclosporin". The resulting formulation, described as a "clear solution", is used directly in animal models to investigate relative lymph node absorption. The solubility of "cyclosporin" in H ₂ O is very low, if the surfactant used is small, it is evident that the claimed solution is an artificial product of sonication method. The "cyclosporin" concentrations achieved are unsuitably low, e.g. for oral dosage forms, and the formulation is inherently unstable, making it virtually excluded as a practical or commercial formulation of any kind. There is. It is essentially just an experimental system that enables laboratory research. No use of detergents has been proposed in any other part of the specification except for lymph node delivery.

Similarly, Japanese Patent Application No. 62-193129 (Japanese Patent Application Laid-Open No. 1-038029) by Takada et al. Discloses, for example, sucrose, sorbitol, tartaric acid, urea, cellulose acetate phthalate, methacrylic acid / methyl together with a small amount of a surfactant. Disclosed is a powder formulation containing cyclosporine dispersed in a solid non-surfactant carrier phase comprising methacrylate or hydroxypropylmethyl cellulose phthalate. In addition, a surfactant is added together with an object to enhance lymphatic delivery, and within the meaning of this specification, this application is obviously the above-mentioned Japanese Patent Application No. 60-71682 (JP-A-61-280435).
No.) is intended to provide practical means for the purpose of applying the doctrine. The sucrose ester as a possible surface-active ingredient is omitted here. Of the list of possible surface-active ingredients, sorbitan esters are reserved. However, Nikkor HCO60 type products have also been shown to be preferred as surfactants, with Nikkor HCO60 being the only surfactant used in the examples. It has not been shown that the alleged improved lymphatic delivery provides any practical benefit or overcomes some of the aforementioned problems with cyclosporine therapy that the industry has faced so far, for example. .

[Structure of the Invention] The present invention relates to fatty acid saccharides as main carrier components.
Provided are novel cyclosporin formulations containing monoesters. These solve or substantially reduce the problems with cyclosporine, eg, "cyclosporine," therapy that the industry has faced so far. In particular, the compositions of the present invention allow for the preparation of solid, semi-solid and liquid compositions containing cyclosporine in a concentration high enough to allow, for example, conventional oral administration, while at the same time providing, for example, bioavailability properties. It has been found to achieve improved efficacy with respect to.

More particularly, the composition according to the invention simultaneously enhances absorption / bioavailability levels and achieves absorption / bioavailability achieved both in individual patients undergoing cyclosporine therapy and also between individuals. It has been found to allow effective cyclosporine administration with reduced variability in bioavailability levels. By applying the teachings of this invention, cyclosporine dosage forms can be obtained that reduce the variability of cyclosporine blood / serum levels achieved between doses for individual patients and between individuals / individual patient groups. That is, the present invention allows for the reduction of cyclosporine dose levels needed to achieve effective treatment. Furthermore, the present invention allows for finer standardization and optimization of ongoing daily dose requirements for individual subjects receiving cyclosporine therapy and groups of equally treated patients.

Dose rate and blood / serum level response of individual patients,
And more precise standardization of dose and response parameters for patient groups can reduce monitoring requirements, ie, substantially reduce treatment costs.

By reducing the required cyclosporine dose / standardizing the bioavailability profile achieved, the present invention also provides for the following in patients receiving cyclosporine therapy:
It provides a means by which the occurrence of unwanted side effects, especially nephrotoxic reactions, can be reduced.

Furthermore, the invention allows the production of compositions which are non-alkanol-based, for example can be ethanol-free or substantially free. These compositions avoid the aforementioned stability and associated processing problems typical of known alkanol compositions. That is, the present invention is particularly adapted by formulating, for example, in the form of capsules, such as gelatin hard or soft capsule forms, and / or eliminates or substantially eliminates the packaging problems described above, eg, with respect to gelatin soft encapsulated forms. Provided is a composition for reducing the above.

More specifically, the present invention comprises: a) cyclosporine as an active ingredient, b) a fatty acid saccharide monoester and c) a diluent or carrier, wherein (i) component (c) comprises components (a) and (b). A solvent for both, wherein components (a) and (b) each independently have a solubility of at least 10% in component (c) at ambient temperature, or (ii) component (c) is component (a) A solvent for both (b) and (b), wherein components (a) and (c) are present in the composition in a ratio of 1: 0.5 to 50 ppw [(a) :( c)], or (iii) Component (c) is a solvent for both component (a) and (b) and the composition is formulated in a solid unit dosage form suitable for oral administration, or (iv) component (c) is , At an average molecular weight of at most 7,000 or at most 15,000 mPa.s. at 50 ° C Poly with a degree -
(C ₂ - ₄ alkylene) - or glycols, or C ₃
- ₅ alkylene polyol ester or comprises or ester, or, (v) or the composition is non-aqueous or substantially non-aqueous, or is (vi) component (c), a solid polymeric carrier, organic oxidizing Silicon polymer (organo-silicon oxide polymer) or paraffinum per-liquidum or paraffinum sub-liquidum
And wherein component (a) is present in said composition as a solid solution in (b).

The composition as defined above is described in French patent application 8811953 and USSN 07/243577, DOS 38304945,
Japanese Patent Application No. 63-231396 and British Application No. 8821
No. 443.9 (First published in France, March 1989 1
It is a novel and particularly advantageous modification of the subject matter claimed generically in corresponding applications in other world countries, including 7th day 2620336).

It should be understood that the above definitions (i) to (vi) are compatible with each other. That is, the composition of the present invention is
Includes 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)-
According to any two or more of (v).

As used in this specification, including in the claims, the term "pharmaceutical composition" refers to a composition as defined in which the individual ingredients or materials are themselves pharmaceutically acceptable, eg It should be understood that when oral administration is expected, it is acceptable as oral, and when topical administration is expected, it is acceptable as topical.

A preferred cyclosporine as component (a) is "cyclosporin". More preferred component (a) is
Also known as cyclosporin G [Nva] ² −
It is "cyclosporine".

Preferred component (b) used in the composition of this invention
Is a water-soluble fatty acid saccharide monoester, for example a fatty acid of a saccharide which has a solubility in water of at least 3.3% at ambient temperature, ie is soluble in water in an amount of at least 1 g of monoester per 30 m of water at ambient temperature. It is a monoester.

The fatty acid portion of component (b) may include 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, especially lauric acid saccharide monoesters.

The saccharide moiety of component (b) may contain suitable sugar residues such as mono-, di- or tri-saccharide residues. 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 sucrose monocaproate, sucrose monolaurate, sucrose monomyristate, sucrose monooleate, sucrose 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) is suitably at least 80%, more preferably at least 90%, most preferably at least 95%.
It has an ester residue purity of. Component (b) suitably has a melting point of about 15 ° C to about 60 ° C, more preferably 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 (a)
Both components (b) and (b) are materials that exhibit a considerable solubility at ambient temperature, for example at a temperature of about 20 ° C. Preferred components (c) are such 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%.
A material having a solubility of (for example, when the component (a) or (b) independently has a solubility of at least about 100 mg, preferably 250 mg, most preferably at least about 500 mg / m). Particularly preferred material conditions are such that component (a) is at least 10%, preferably at least 25%.
%, Most preferably 50% and / or component (b) is at least 100%, more preferably at least 200%, most preferably at least 3%.
It has a solubility of 00% (for example, the component (b) has a solubility of at least 1000, more preferably 2000, and most preferably at least 3000 mg / m 2).

Component (c) suitable for use in the compositions 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 or esters and mixtures thereof.

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

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) C _{3 5} alkylene triol,
Most preferred is glycerin.

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, those ingredients are preferably at most about 7000 [see definition (vi)], for example 6600 or less, more preferably at most about 20.
It has an average molecular weight of 00, for example 1600 or less, most preferably at most about 500. Preferably, those ingredients are 50
℃ or more preferably at ambient temperature, at most about 15000 m
Pa.s., more preferably at most about 1000 mPa.s., most preferably at most about 200 mPa.s. [see definition (iv)]. Suitable polyethylene glycols for use as component (c) are, for example, Fiedler, "Lexikon der Hilfstoff".
offe), 2nd revision and expansion, (1981) Volume 2, 726
~ 731, especially PEG products (polyethylene glycols) 200, 300, 400 and 600 and PEG100.
0, 2000, 4000 or 6000, in particular 200, 300 and 400, for example substantially according to the physical properties below.

Component (c) C ₃ - ₅ when containing alkylene polyol ethers or esters (c ^5), which is preferably C ₃ -
₅ Alkylenetriols, especially glycerin, 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 Includes 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.

Particularly suitable components (c ⁵ ) for use according to the invention are glycerins such as 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. These transesterification products, generally, poly - (C ₂ - ₄ alkylene) glycols, e.g. glycerides in the presence of glycerol by polyethylene glycol and, optionally,
For example, it is obtained by alcoholysis of triglycerides (that is, by transesterification of glyceride to poly-alkylene glycol / glycerin component, that is, by poly-alkylene glycolysis / glycerin degradation). In general, the reaction is carried out by reaction of the indicated components (glyceride, polyalkylene glycol and optionally glycerin) under an inert atmosphere at elevated temperature with continuous stirring.

Preferred glycerides include fatty acid triglycerides, such as (C ₁₀ −), including natural and hydrogenated oils, especially vegetable oils.
₂₂ fatty acids) triglycerides. Suitable vegetable oils include, for example, olives, almonds, peanuts, coconuts,
Palm, soybean and wheat germ oils and, in particular (C ₁₂ - ₁₆
There are natural or hydrogenated oils rich in (fatty acid) ester residues.

Preferred polyalkylene glycol materials are polyethylene glycols, especially about 500 to about 4000, for example about 1000.
~ Polyethylene glycols having a molecular weight of 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) glycols, C in relative amounts that may vary ₃ - ₅
Alkylenetriol esters such as mono-, di-
And tri - comprises a mixture of esters - esters and poly (C ₂ - ₄ alkylene) glycol mono - and di. As mentioned earlier in this specification, the preferred alkylenetriol 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 .

That is to say, in other words, a particularly suitable component (c ⁵ ) is a transesterification product of natural or hydrogenated vegetable oils and polyethylene glycol and optionally 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 may be defined or including (which may include optionally example minor amounts of free glycerol and free polyethylene glycol together) or those as a composition whose components.

Preferred vegetable oils, polyethylene glycols or polyethylene glycol moieties and fatty acid moieties with respect to the above definitions are as described above. The particularly suitable component (c ⁵ ) described above for use in the present invention is gelsyl (Gelu
cir) known products marketed under the trade name, in particular i) Gelsyl 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) Gelsyl 37/02, melting point = about 34-40 ° C and saponification number =
About 200-220, iv) Gelsyl 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) Gelsyl 46/07, melting point = about 47-52 ° C and saponification number =
About 125-145, vii) Gelsyl 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) Gelsyl 62/05, melting point = about 60-65 ° C and saponification number =
It is a product of about 70-90.

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

The component (c) specifically mentioned above [that is, the component according to any of the above definitions (i) to (iv) or (c ¹ ) to
When the component described in the item (c ⁵ )] is used, the composition of the present invention generally contains the component (a) in a carrier medium containing the components (b) and (c). Typically, components (a) and (b) are each a dispersion or solution of the composition of this invention,
For example, it is present in the form of 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), while component (b) is present in a solution containing (c). Component (b) generally acts as a carrier or solubilizer (pre- and / or post-administration) for component (a) in the compositions of this invention, and component (c)
Acts as a carrier or superplasticizer. (Of course, this invention should not be understood as limiting in any way to the particular functional relationship between components (a), (b) and (c) unless otherwise stated.) When using component (c) as described above, the composition of the invention is preferably formulated as a solid unit dose form suitable for oral administration, eg a gelatin hard or soft capsule form suitable for oral administration [Definition (Iii)].
Those unit dose forms will be described in more detail below,
Suitably, for example, 2-200 mg of component (a) is contained per unit dose.

When using the aforementioned component (c), the components (a) and (c) are preferably 1: 0.5 to 50 ppw [(a) :( c)].
It is present in the composition of the invention in the proportion [see definition (ii)]. Components (a) and (b) are preferably 1: 3 to 200 pp
It exists in the ratio of w [(a) :( b)].

When the above-mentioned component (c) is used, the composition of the present invention is further non-aqueous or substantially non-aqueous [see Definition (v)], for example, the water content based on the total weight of the composition is It 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: a diluent selected from said component (a) and component (b) and any ^{one of} said components (c ¹ ) to (c ⁴ ), or including mixtures thereof, as defined above (ii) ~ pharmaceutical composition according to any one of (v), - the components (a), comprises (b) and (c ^2), the definition (ii), (iii) or a pharmaceutical composition according to (v), and - the components (a), provides a pharmaceutical composition comprising (b) and (c ^5).

Component (c) specifically mentioned above [ie definition (i)
~ A component according to any one of (iv) or (c ¹ ) ~
If the (c ⁵⁾ one of components] As used in the compositions of the present invention, components (a) and (c) is suitably from about in the composition 1: present in proportions 0.5~50ppw . More preferably, components (a) and (c) are about 1: 1-10, more preferably 1: 1-5, most preferably about 1: 1.5-2.5, such as about 1: 1.6 or 1: 2 ppw. It exists in the ratio of [(a) :( c)]. Components (a) and (b) are suitably present in the composition in a proportion 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 to 10, most preferably about 1: 6.0 to 6.5, for example about 1: 6.2.
It exists at a ratio of 5 ppw [(a) :( b)].

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

A composition according to the invention comprising component (c) as defined above may be used, for example, for intralesional injection in the treatment of autoimmune conditions of the eye, such as the aforementioned conditions or for example of psoriasis, eg oral, parenteral or topical application eg dermal. Alternatively it may be manufactured in a dosage form suitable for ophthalmic application, eg application to the surface of the eye.

Suitably, the compositions, whether for oral administration or otherwise, are prepared in unit dose form.

Of course, the component (a) present in those unit dose forms
Will vary depending on, for example, the condition being treated, the intended mode of administration and the desired effect. However, in general,
Such unit dosage forms are suitably from about 2 to about 200 mg of component (a) per unit dose, eg "cyclosporin".
Contains.

Suitable dosage forms for oral administration include eg liquids, granules and the like. However, preference is given to solid unit dose forms, for example tablets or encapsulated forms, especially gelatin hard or soft capsule forms. These oral unit dosage forms are preferably from about 5 to about 200 mg, more preferably from about 10 or 20 to about 100 mg, for example 15, 20, 25, 5 per unit dose.
It contains 0, 75 or 100 mg of component (a), eg "cyclosporin".

The compositions according to the invention comprising said component (c) show that they exhibit modified release properties such as delayed release of component (a) or prolonged release of component (a) after oral administration. It has the further advantage of providing a base for the composition. The compositions further include component (d) that can modify the release profile of the composition with respect to component (a). Those components (d) are, 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:

d ¹ ) Polyacrylates 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, Fiedler,
See supra 1 , page 206-207), especially Carbopol products 93
4, 940 and 941 and Eudragit (see Fiedler, supra, 1 , pages 372-373), especially Eudragit products E, L, S, RL and RS, most particularly 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 salts thereof 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 (Fiedler, supra, 1 ,
Pp. 521 and 2 , p. 601), especially Krusel LF, MF, GF
And HF and Methocel K100, K15M, K100M, E5M, E1
There are products such as 5, E15M and E100M.

d ³ ) Polyvinylpyrrolidones, such as poly-N-vinylpyrrolidones and vinylpyrrolidone copolymers,
For example, vinylpyrrolidone-vinyl acetate copolymer. Examples of said compounds suitable for use according to the invention are known.
For example, Kollidon (Fiedler, supra,
1 , page 526 and 527), and especially Kollidon products 30 and 90.

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

d ⁵ ) Silicon dioxides, eg hydrophilic silicon dioxide products, eg alkylated (eg methylated) silica gels, in particular the known colloidal silicon dioxide products marketed under the tradename Aerosil [“Handbook of
Pharmaceutical Excipients "(Handbook
of Pharmaceutical Excipients), published by Pharmaceutical Society of Great Britain, pp. 253-256], especially Aerosil products 130, 2
00, 300, 380, O, OX50, TT600, MOX80, MOX170, LK84
And methylated Aerosil R972.

When component (d) is present, it is preferably about 0,0 based on the total weight of components (a) + (b) + (c) + (d).
It is present in an amount of 5-50% by weight, more preferably about 1-20% by weight, most preferably about 2-10% by weight.

If component (c) in the composition of this 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. It is a sexual carrier.

Particularly preferred as component (c ^6), polyvinylpyrrolidones [Fiedler, supra, 2, pp 748-750], in particular cross-linked polyvinyl pyrrolidones. Examples of those materials suitable for use in the present invention are known and include Kollidon [Feedler, supra, see 1 , 527], Kollisept [Feedler, supra, see 2 , 719-720], povidone (povidone) and crospovidone (crospovidone) [Fiedler, supra, 2, 751 pp. Browse commercially available under the trade name.

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, for example about 40,000 or more. Cross-linked polyvinylpyrrolidones are of particular interest. Examples of specific products suitable for use in this invention as (c ⁶ ) include Plasdone X
There are L, Plasdon XL10 and Crospovidone.

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

Yet another example of those materials of particular interest for the composition of the present invention comprising component (c ⁶ ) is Avicel (Avic
el) [Fiedler, supra, 1, pp. 160-161], Erusema (Elcema) [Fiedler, supra, 1, 326 pp.]
And Pharmacoat [Fiedler,
See page 2 , 707, supra], known products such as Avicel PH101 and PH102, Elsema and Pharmacoat 603 products.

In the case of the composition of the invention comprising component (c ⁶ ), component (a) is present in component (b) which is a solid solution, eg a complete or substantially complete solid micellar solution, a molecule or a micellar 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. Therefore, the term "solid solution" as used in this specification, including the claims, should be construed as including, for example, viscous or highly viscous systems]. The solid solution containing (a) and (b) as a component is preferably in the component (c ⁶ ),
For example, it is dispersed throughout the component (c ⁶ ) in the form of, for example, particles. That is, the component (c ⁶ ) generally functions as a collapsible matrix for [(a) + (b)] in the composition of the present 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. Materials suitable for use as binders / lubricants include, for example, fatty acids /
Fatty acid and alkyl sulfonates having 10 or more carbon atoms in the alkyl moiety, for example, metal salts, for example C ₁₀ - ₂₂ fatty acids 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 [Fiedler, supra, 2 , p. 584].

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

Component (c ⁶ ) is suitably present in the composition of the invention in an amount of at least 10% by weight, more preferably at least 15% by weight, more preferably at least 20% by weight, based on 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 15
-50% by weight, for example about 20-40% by weight, for example about 25, 30 or 35% by weight, in a composition according to the invention.

If component (d) is present, components (d) and (c ⁶ )
Is preferably about 1: 0.5-4, more preferably about 1: 1-
3, most preferably about 1: 1.5 to 2.5, for example about 1: 2 or about 1: 2.5 ppw in the ratio [(d) :( c ⁶ )].

If component (e) is present, components (e) and (c ⁶ )
Is preferably about 1: 5-25, more preferably about 1: 5-20,
Most preferably from about 1: ratio of ^{7~15ppw [(e) :( c 6} )]
Exists in.

When the composition of this invention comprises all three components (c ⁶ ), (d) and (e), these are preferably about 25-75%, more preferably about 30%, based on the total weight of the composition. ~ 65
%, Most preferably about 40-65% together.
Component ratio [(a) + (b)]: [(c) + (d) +
(E)] is preferably 1: 0.25 to 7.5, more preferably
1: 0.5 to 5, most preferably 1: 0.5 to 2, for example about 1: 0.
It is about 8, 1: 1.2 or 1: 1.3 ppw.

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

Of course, the component (a) present in those unit dose forms
Will vary depending on, for example, the condition being treated, the intended mode of administration and the desired effect. However, in general, they are preferably from about 2 to about 200 mg per unit dose.
Component (a) of, for example, "cyclosporin".

Suitable dosage forms for oral administration include granules and the like. However, preferred is a solid unit dosage form,
For example in tablet or capsule form. The oral unit dosage forms are preferably about 5 to about 200 m per unit dose.
g, more preferably about 10 or 20 to about 100 mg, for example 15,
It contains 20, 25, 50, 75 or 100 mg of component (a), eg "cyclosporin".

Component (c) in the compositions of this invention, (c ⁷⁾ defined above (vi) requires an organic silicon oxide polymers or over is by - or nitrous - if it contains liquid paraffin, component (c ⁷⁾ is preferably Can flow easily at a temperature of 150 ° C. or lower, preferably 100 ° C. or lower, more preferably 50 ° C. or lower. Suitably component (c ⁷ ) is 15000 mPa.s.
More preferably, it has a maximum viscosity of 1000 mPa.s.

Suitable paraffin hydrocarbons for use as component (c ⁷ ) are liquid and semi-solid paraffins and mixtures thereof, namely sub- and para-liquid paraffins [see Fiedler, supra, 2 , 690-691]. .
For ease of formulation, component (c ⁷ ) is preferably composed or essentially composed of fluid or semi-solid paraffins, ie super liquid paraffins or sub liquid paraffins or mixtures thereof. However, if it is desired to produce a composition having, for example, a slower active ingredient release profile, this can be achieved by solid paraffin, or solid (du)
rum) can be achieved by further adding 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 preferably about 1: 6 to 2
00, more preferably about 1: 6 to 100, most preferably 1: 6.
-20, for example about 1: 8 ppw [(a) :( c)].

If the composition according to the invention additionally comprises solid paraffins as component (c ⁷ ), the liquid / semisolid paraffin: solid paraffin component ratio is preferably about 1: 0.06 to 0.1 ppw.
Is. In this case, components (a) and (c ⁷ ) are suitably 1: 6 to 200, more preferably 1: 6 to 100, most preferably 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 designated as methyl or phenyl) are included. Particularly preferred is about 0.65 to 10 ⁵ cP, especially about 10 or 50 to 500 or 1000.
It is an organosiloxane polymer having a viscosity of cP.

For ease of formulation, component (c ⁷ ) is preferably a liquid organosiloxane polymer, such as a poly-methylsiloxane polymer, such as any of the various known silicone oils, such as silicone oil 550, DC200, SF-1066. And SF-1091
[See Fiedler, supra, 2 , p. 826]. When the composition according to the invention comprises only liquid organosiloxane polymers, the components (a) and (c ⁷ ) are preferably present at about
1: 6 to 200, more preferably from about 1: 6 to 100, and most preferably from 1: 6 to 20, such as about 1: ratio of ^{8ppw [(a) :( c 7} )]
Exists in.

For example, a composition having a slower active ingredient release profile may be a semi-solid organosiloxane polymer as component (c ⁷ ) such as any of the various known silicon pastes, such as silicon paste A [Fiedler, supra, 2 , 826. Reference] or by adding them to, for example, the other organosilicon oxide polymers mentioned above. In the latter case, the ratio of liquid: semisolid organosilicon polymer present in the composition of this invention is preferably on the order of about 1: 0.5 to 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 the abovementioned components (c ⁷ ) can also be used in the compositions 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 to 10, and most preferably about 1: 6.0-6.5, for example about
It exists in the ratio [(a) :( b)] of 1: 6.25 ppw.

In the case of the composition of the invention comprising component (c ⁷ ), component (a) is present in component (b) in the form of a completely or substantially completely molecular or micellar dispersion, eg a solid solution or a solid micellar solution. [However, the term “solid solution” is used herein in the same broad sense as composition (c ⁶ ) with respect to 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.

The composition according to the invention comprising component (c ⁷ ) is for example for the treatment of autoimmune conditions of the eye, for example the conditions mentioned above, or for intralesional injection, for example in 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, for example application to the surface of the eye. Suitably they are manufactured in unit dosage form, whether for oral administration or by other methods of administration.

Of course, the amount of component (a) present in those unit dosage forms will vary depending, for example, on the condition being treated, the intended mode of administration and the desired effect. However, in general,
They preferably contain from about 2 to about 200 mg of component (a) per unit dose, eg "cyclosporin".

Suitable dosage forms for oral administration include liquids, granules and the like. However, preferred is a solid unit dosage form,
For example tablets or encapsulated forms, especially gelatin hard or soft capsule forms. These oral unit dosage forms are preferably about 5 to about 200 mg, more preferably about 10 or 20 to about 100 mg per unit dose, eg 15, 20, 25, 5
It contains 0, 75 or 100 mg of component (a), eg "cyclosporin".

The composition according to the invention comprising component (c ⁷ ) has a modified release profile such that after oral administration, eg delayed release of component (a) or extended component (a).
It has the additional advantage of providing a base for the composition that exhibits properties such as the release of These compositions may be prepared in manner by encapsulating a solid or semi-solid component (c ⁷⁾ in an appropriate amount. Alternatively, they may be prepared by including additional component (d): a component that may modify the release profile 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, and agents which are swellable in water, such as water-swellable polymers or colloids, such as those mentioned above. d ¹⁾ includes any ~ (d ⁵⁾ as defined in claim material.

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

Component (d ⁵ ) is particularly suitable for use in the composition according to the invention which contains an oxidized organosilicon 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, or preferably as described above for a composition comprising other component (c), or preferably That is the state.

The composition according to the invention comprises selected components (c) [eg,
The component (c) is any one of the above-mentioned components (c ¹ ) to (c ⁷ )
One or a mixture thereof] or
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 (BH).
T)], flavoring agents and the like.

In particular, the composition according to the invention also preferably comprises one or more stabilizers or buffers to prevent hydrolysis of component (b) or decomposition of component (a), especially during processing or storage. including. Those stabilizers 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.

The stabilizers or buffers are preferably about 3-8,
More preferably, it is added in an amount sufficient to achieve or maintain a pH in the range of about 5-7, for example 6-7.
These stabilizers are generally not more than 5% by weight, based on the total weight of the composition, for example when using citric acid or acetic acid,
Or it is present in an amount up to 10% by weight. Compositions according to the invention having a pH within the above range, especially those in which component (a) is "cyclosporin" are preferred.

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 sulphate or phospholipids such as lecithin. Including kind. If present, it is suitably 5 to 50, more preferably 10 to 50, for example 10 to the weight of component (b).
Present in an amount of ~ 25%.

For the composition of the invention comprising component (a) as a solid solution in component (b), for example, when component (c) is the above-mentioned component (c ⁶⁾ or (c ^7), stabilizers described above, buffer And / or the surfactant is preferably incorporated in the solid solution phase. Those materials may also be included in component (c) and the like.

The composition according to the invention also comprises the selected component (c).
Independently of, preferably ethanol-free or substantially ethanol-free, for example 5.0 based on the total weight of the composition.
%, More preferably less than 2.5%, eg 0-1.0%
Including ethanol.

In addition to the above, the invention also provides a method for producing the pharmaceutical composition, wherein the components (a), (b) and (c) are optionally combined with the components (d) and / or other components, A unit dose of the resulting composition is obtained, for example, by intimate mixing or formulation with the above-mentioned stabilizers, buffers or surfactants and, if necessary, for example by tabletting, filling into gelatin capsules or other suitable means. Methods are provided that include formulating a dosage form, eg, a unit dosage form for oral administration.

The component (c) is a solvent for the components (a) and (b), or the aforementioned components (c ¹ ), (c ² ), (c ³ ),
When (c ⁴ ) or (c ⁵ ) is included, the components (a), (b) and (c) are suitably warmed, for example at temperatures below 50 ° C to 150 ° C, preferably not exceeding 70 or 75 ° C. While combining components (a) and (b) together in component (c) together in the above process. 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, by filling gelatin hard or soft capsules at a suitably high temperature, for example 50 ° C or lower,
For example, to achieve fluidity of the composition in warm air.

A composition according to the invention comprising component (a) as a solid solution in component (b), such as component (c ⁶ ) or (c ⁷ ) described above.
In the case of a composition comprising, the method preferably comprises first (b)
A step of producing a solid solution containing the medium (a) and then intimately mixing or blending the obtained solid solution with the remaining components (c) and optionally (d) and the like.

The solid solution containing the component (a) in the (b) solidifies a melt containing the solution of the (a) in the (b), or the solid solution containing the component (a) and the (b) according to the known technique in the art. Can be prepared by removing the solvent from the solution consisting of The latter method is generally preferred for the purposes of this invention.

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

The solid solution thus obtained is then, for example, preferably distributed in component (c), for example in the form of fine particles of component (c) and optionally components (d) and (e).
And so on.

Ethanol can be used for the purpose of producing the composition of the invention, for example in the production of said solid solution, which is
It is preferably removed, for example by evaporation before completion of the final dosage form, resulting in the ethanol-free or substantially ethanol-free product described above.

[Example]   The present invention will be described below with reference to examples.

The product sucrose monolaurate L-1695 used in the examples is a product of Mitsubishi Kasei Foods Co., Ltd. (Tokyo, Japan 10
4) commercially available from HLB value = at least 12.3, lauryl ester residue purity = at least 95%, MP = about 35 ° C,
Decomposes at about 235 ℃, surface tension of 0.1% by weight aqueous solution = about 25 ℃
72.0 dyn / cm.

Example Component Relative amount (mg) 1.a) Cyclosporine (eg, "cyclosporin") 50.0 b) Sucrose monolaurate L-1695 312.5 c) 1,2-Propylene glycol 100.0 Total 462.5 2.a) Cyclosporine For example, "cyclosporin") 50.0 b) Saccharose monolaurate L-1695 312.5 c) Glycerin 100.0 Total 462.5 3.a) Cyclosporine (eg, "cyclosporin") 50.0 b) Saccharose monolaurate L-1695 312.5 c) PEG200 100.0 Total 462.5 4.a) Cyclosporine (eg, “Cyclosporin) 50.0 b) Saccharose monolaurate L-1695 312.5 c) PEG400 100.0 Total 462.5 5.a) Cyclosporin (eg,“ Cyclosporin) 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) Shikurosupori (Eg, "cyclo Suporin) 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) Cyclosporin (e.g.," cycloalkyl Suporin) 50.0 b) Sucrose monolaurate L-1695 350.0 c) 1,2-Propylene glycol 100.0 d) Aerosil 200 15.0 Total 515.0 8.a) Cyclosporine (eg "cyclosporin" 50.0 b) Sucrose monolaurate L-1695 350.0 c ) PEG400 200.0 d) Eudragit L 2.5 Total 602.5 9.a) Cyclosporine (eg "cyclosporin) 50.0 b) Sucrose monolaurate L-1695 312.5 c) Gelsyl (eg Gelsyl 42/12, 44/14 or 35/10) 100.0 Total 462.5 10.a) Cyclosporine (eg "cyclosporin) 50.0 b) Sucrose monolaurate L-1695 312.5 c) Gelsyl 100.0 d) Klucel 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 2-10 are prepared in a similar manner. In the case of Examples 5 and 8,
Ingredient (d) is dissolved in the initially obtained mixture of ingredients (a)-(c). In the case of Examples 6, 7 and 10, component (d) is suspended in (a)-(c).

The resulting composition is filled into gelatin hard capsules, size 1 (Examples 1 to 4 and 9) or size 0 (Examples 5 to 7 and 10) while warming to give the encapsulated final product. To be Each capsule contains 50 mg of cyclosporine (eg, "cyclosporin") and is suitable for administration in the prevention of transplant rejection or the treatment of autoimmune diseases, for example 1 to 5 capsules daily.

Example Ingredients Relative amount (mg) 11.a) Cyclosporine (eg, "Cyclosporin" 100.0 b) Sucrose monolaurate L-1695 300.0 c) Plasdone 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 ) Sucrose monolaurate L-1695 350.0 b ² ) Sucrose monostearate 50.0 c) Crospovidone 250.0 d) Elsema 150.0 e) Magnesium stearate 30.0 Total 980.0 13.a) Cyclosporine (eg "cyclosporin) 50.0 b) Sucrose monolaurate L-1695 160.0 c) Plasdon XL10 200.0 d ¹ ) Pharmacote 603 25.0 d ² ) Avicel PH 101 75.0 e) Magnesium stearate 20.0 Total 605.0 Compositions 11 to 13 above preferably each further contain 25 mg (f) tartaric acid and / or 50 mg (g) diester. Chi succinate, preferably comprising both, final weight, when the composition 11 1000 mg, for compositions 12 1055Mg and composition
In the case of 13, it will be 6180 mg.

Compositions 11-13 are manufactured as follows. Components (a) and (b) are dissolved in absolute ethanol and the ethanol is thoroughly evaporated under reduced pressure at 50 ° C. Thoroughly mix components (c)-(e) using conventional mixing techniques [add (f) and (g) if used). [(A) +
The solid solution containing (b)] is pulverized into a fine powder, and [(c)-
(G)] and mixed uniformly into the
Administration in the prevention of transplant rejection or treatment of autoimmune diseases, for example from 1 to 1 day, containing 100, 50 or 25 mg of (a).
Compress into tablets suitable for administration of 5 tablets.

Examples Ingredients Relative amount (mg) 14.a) Cyclosporine (eg, "Cyclosporin" 50.0 b) Sucrose monolaurate L-1695 312.5 c) Superfluid paraffin 397.5 Total 760.0 15.a) Cyclosporine (eg, "Cyclosporine" Sporine) 50.0 b) Sucrose monolaurate L-1695 312.5 c) Silicon oil DC200 397.5 Total 760.0 Dissolve components (a) and (b) in absolute ethanol,
Thoroughly evaporate the ethanol under reduced pressure at 50 ° C. The obtained solid solution is ground into fine powder and uniformly suspended in the component (c). Filling the resulting liquid suspension into hard gelatin capsules, size 0, gives the final product encapsulated. Each capsule contains 50 mg of cyclosporine (eg, "cyclosporin") and is suitable for administration in the prevention of transplant rejection or the treatment of autoimmune diseases, for example 1 to 5 capsules daily.

Examples Ingredients Relative amount (mg) 16.a) Cyclosporine (eg, "Cyclosporin" 50.0 b) Sucrose 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) Sucrose monolaurate L-1695 312.5 c) Superfluid paraffin 397.5 d) Aerosil 10.0 Total 770.0 Compositions 16 and 17 are also prepared in the same manner as 14 and 15 above. In the case of the product 16, (c) and (d) are first combined by melting, and the mixture is intimately stirred together, and then a solid solution containing [(a) + (b)] is mixed with [(c) +].
(D)]. For composition 17, (d) is suspended in (c) with [(a) + (b)].

Compositions equivalent to the compositions of Examples 1 to 17 above were prepared by substituting "cyclosporin" as component (a) with another cyclosporine, for example [Nva] ^2- "cyclosporine", or as component (b) sucrose. It can be prepared, for example, by replacing monolaurate with another fatty acid saccharide monoester as described above, for example raffinose monolaurate, but in each case in the same or equivalent amounts or in relative proportions.

The utility of the composition according to the invention can be demonstrated, for example, in animal or clinical trials carried out as follows.

Bioavailability test for compositions 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 of 8 Beagle dogs (male, about 11-13 kg) is used. Animals are not fed within 18 hours of administration of the test composition, but have free access to water until the time of administration.
The test composition was administered by gavage, followed by NaCl 0.
Administer 20m of 9% solution. 3 hours after administration of the test composition,
Keep animals free access to food and water.

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

Blood samples are analyzed by RIA. Calculate the area under the blood drug concentration versus time curve by the trapezoidal rule. Analysis of variance was performed by AUC (area under the curve), Cmax (maximum concentration) and Tmax
(Maximum time).

c) Results Average AUC (ng · h / m) calculated from typical test course
⁻¹ ) and Cmax (ng / m ⁻¹ ) values are shown in the table below along with the calculated variability (CV) in the response between test animals that received the same composition.

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

Comparable advantageous results are also obtained with other compositions according to Examples 1 to 17 above, especially the compositions of Examples 1 to 10.

Clinical Trials The advantageous properties of the compositions according to the invention in oral administration can also be demonstrated in clinical trials carried out eg in the following manner.

The test subjects are adult volunteers, such as men aged 30 to 55 who have received specialized education. The test group preferably consists 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 interfere with drug absorption, distribution, metabolism, excretion or safety, clinically significant signs of disease in the 2 weeks prior to study, clinically significant abnormal laboratory values. Or electrocardiogram, the need for ancillary care during the whole course of the study, administration of a drug known to have well-defined potential toxicity to major organ systems within 3 months before the study, 6 weeks before the start of the study Administration of study drug, history of drug or alcohol dependence, blood loss of 500m or more within the last 3 months, drug side effect or hypersensitivity, history of allergy requiring drug treatment, hepatitis B / HIV positive .

Complete physical examination and ECG before and after the test. The following parameters are evaluated within 1 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, red blood cells,
Ketone body, precipitate.

Creatinine clearance is also measured one month before the start of the test.

Each subject receives the test composition in a random order. The composition is administered orally (one total dose of 150 mg cyclosporine, eg "cyclosporin"), with at least 14 days between each administration.

Administration is performed in the morning after a 10-hour overnight fast (however, only water is observed). Only caffeine-free beverages are permitted within 24 hours after administration. Subjects will not smoke within 12 hours after administration. Four hours after dosing, subjects are given standard lunch.

1 hour before administration and 0.25, 0.5, 1, 1.5 before administration,
2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 9, 12, 14, 2
Blood samples (2 m) are taken after 4, 28 and 32 hours.
To measure creatinine, 2m blood samples are taken immediately before administration and at 12, 24 and 48 hours after administration. Samples for cyclosporine measurement were collected in 2 EDTA-coated polystyrene tubes (1 m each) at each time point, and after gentle agitation −20
Quick-freeze at ℃. Cyclosporin in whole blood is measured using RIA by specific and / or non-specific MAB assay. Detection limit in both cases = approximately 10 ng / m.

In the tests carried out according to the above protocol, the composition of Example 1, for example in the form of hard gelatin capsules, was used as standard for "cyclosporin" drinking solution ("cyclosporin" = 50).
mg, labrafil = 150 mg, ethanol = 50 mg, corn oil = 213 mg, final weight of contents in soft gelatin capsule form = 463 mg / dose)
A significant increase in bioavailability levels is recorded for the composition of Example 1 as compared to the standard, as reflected in both C (0-32 hours) and Cmax values. further,
Comparison of changes in whole blood “cyclosporin” concentration (measured by specific monoclonal RIA) over time after a single dose of test composition (150 mg “cyclosporin” dose), for all subjects receiving standard composition It is demonstrated that the variability in response between all subjects administered 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 the invention, such as the compositions described in the examples.

─────────────────────────────────────────────────── ─── Continuation of the front page (31) Priority claim number 8903663.6 (32) Priority date February 17, 1991 (February 17, 1989) (33) Country of priority claim United Kingdom (GB) (72) Inventor Ulrich Pozanski Federal Republic of Germany Day-7800 Freiburg, Inden Kirchenmatten No. 2 (56) Reference JP-A-1-151526 (JP, A) JP-A 64-38029 (JP, A) JP 61-280435 (JP, A) Pharm. Res. , Vol. 3, No. 1 (1986), p48-51 (58) Fields investigated (Int.Cl. ⁷ , DB name) A61K 38/13 A61K 47/26 A61K 47/34

Claims (15)

(57) [Claims] 1. A pharmaceutical composition comprising (a) cyclosporine as an active ingredient, (b) a fatty acid saccharide monoester, and (c ² ) 1,2-propylene glycol, which comprises (ii) component (a) And (c ² ) is 1: 0.5 in the composition.
˜50 ppw [(a) :( c ² )], or (iii) the composition is formulated in a solid unit dosage form suitable for oral administration, or (v) A pharmaceutical composition, wherein the composition has a water content of less than 20%. 2. A pharmaceutical composition containing (a) cyclosporine as an active ingredient, (b) a fatty acid saccharide monoester, and (c ⁵ ) C _3-5 alkylene polyol ether or ester. 3. Component (c ⁵ ) comprises a transesterification product of natural or hydrogenated vegetable oil and polyethylene glycol.
The composition according to claim 2. 4. Component (c ⁵ ) is a natural or hydrogenated vegetable oil and
The composition of claim 3 comprising a transesterification product of polyethylene glycol having a molecular weight of 500 to 4000. 5. The composition according to claim 3 or 4, wherein component (c ⁵ ) comprises a transesterification product of natural or hydrogenated vegetable oil, polyethylene glycol and glycerin. 6. A composition according to claim 2, wherein components (a) and (c ⁵ ) are present in a ratio of 1: 0.5 to 50 ppw. 7. The components (a) and (c ² ) (in the case of claim 1) or (c ⁵ ) (in the cases of claims 2 to 5) are 1: 1 to 10 ppw.
The composition according to any one of claims 1 to 6, which is present in a ratio of [(a) :( c ² ) / (c ⁵ )]. 8. The components (a) and (b) are 1: 3 to 200 ppw.
The composition according to any one of claims 1 to 7, which is present in a ratio of [(a) :( b)]. 9. Unit dose form, 2 to 20 per unit dose
A composition according to any one of claims 1 to 8 comprising 0 mg of component (a). 10. The composition according to claim 1, further comprising a stabilizer or a buffer. 11. The composition of claim 10 buffered to a pH of 3-8. 12. The component (a) is “cyclosporin” or [Nva] ^2- “cyclosporin”, according to claims 1 to 11.
The composition according to any one of 1. 13. The composition according to claim 1, wherein component (b) comprises a water-soluble fatty acid saccharide monoester. 14. The composition according to claim 13, wherein component (b) comprises a C _6-18 fatty acid di- or tri-saccharide monoester. 15. The composition of claim 14, wherein component (b) comprises raffinose or sucrose monolaurate.