JPH0611703B2 - New cyclosporin formulation - 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 with a unique structure, which usually have pharmacological properties, particularly immunosuppressive, anti-inflammatory and / or antiparasitic activity. Includes. The first of the cyclosporins to be isolated, also known as cyclosporin A, is Sandimun (SANDIMMUN or SANDIMM
A natural fungal metabolite "Ciclosporin" (Ciclosporin or Cyclosporine) marketed under the trade name of (UNE)
Met. "Cyclosporine" is cyclosporine represented by formula (A).

(In the formula, -x-y- is -CH = CH- (trans)) N-methyl- (4R) -4-buta-2E-en-1-yl-4-methyl- (L ) Represents a threonyl residue] As this type of matrix, "cyclosporine" has received the most attention so far. The main areas of clinical research on "cyclosporine" are as immunosuppressants, especially organ transplants, such as heart, lung, cardiopulmonary, liver, kidney, pancreas, bone marrow,
It has been related to skin and corneal transplantation and its application to recipients of atypical organ transplants in particular. "Cyclosporine" has gained significant achievements and reputation 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, irreproducible 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 ( For example, 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 part) And posterior), keratoconjunctivitis sicca and spring keratoconjunctivitis, interstitial pulmonary fibrosis, psoriatic arthritis and glomerulonephritis (eg idiopathic nephrotic disease). If not the case or without nephrotic syndrome, including a group or micro lesions nephropathy) is.

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 has been isolated and identified since the initial discovery of cyclosporins, and many other non-natural cyclosporins have been produced by whole or semi-synthetic means or by the application of modified culture techniques. That is, there are many types of cyclosporins,
For example, natural cyclosporin AZ [reference, travers, etc.
1, "Helvetica Shimika Actor" (Helv.Chim.Act
a.) 60 , 1247-1255 (1977), Travers et al. 2, "Helvetica Simica Actor" (Helv. Chi
m.Acta.) 65 , number 162, 1655-1667
(1982), Corbel et al., "European Journal of Applied Microbiology and Biotechnology" (Europ. J. Applied Microbiolog).
y and Biotechnology) 14 , 273-240 (198)
2), and von Bartberg and others, "Progress
In Allergy, 38 , 28
-45 (1986)], and various non-natural cyclosporin derivatives and artificial or synthetic cyclosporins,
For example the so-called dihydro - cyclosporins [in this case, -MeBmt- -x-y- parts by saturating the (above formula B) residues, -x-y - = - CH 2 -CH 2 - can be 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), cyclosporins in which the -MeBmt- residue is present in isomeric form (eg,- (If the configuration between the 6'and 7'positions of the MeBmt-residue is cis rather than trans), and the use of the total synthetic cyclosporin production method developed by, for example, Wenger, allows the variant amino acid to be identified in the peptide sequence. Cyclosporins incorporated in position [eg Travers 1, Travers 2 and Corbel, supra, US Pat. No. 41089]
No. 85, No. 4210581 and No. 422064
No. 1, European Patent Publication No. 0034567, No. 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, "Angewante Chemie International Edition in English" (Angew. Chem. Int.
Ed.), 24 , 77 (1985) and Wenger 3,
"Progress in the Chemistry of Organic Natural Products"
hemistry of Organic Natural Products), 50 , 12
3 (1986)].

That is, as the types contained in cyclosporins,
For example, [Thr] ² −, [Val] ² −, [Nva] ² − and [Nva] ² − [N
va] ^5- [cyclosporin] (respectively cyclosporin C,
(Also known as D, G and M), [3'-O-
Acyl-MeBmt] ^1- “cyclosporin” (also known as cyclosporin A acetate), dihydro- [MeBm
t] ^1- [Val] ^2- "cyclosporin" (also known as dihydro-cyclosporin D), 3'-desoxy-3'-oxo- [MeBmt] ^1- [Val] ^2- and-[Nva] ^2-
“Cyclosporine”, [(D) fluoromethyl-Sar] ³ −
^{"Cyclosporine", [(D) Ser] 8} - "cyclosporine", [MeIle] ¹¹ - "cyclosporine", [(D) MeVal] ¹¹
-"Cyclosporin" (also known as Cyclosporin H), [MeAla] ^6- "Cyclosporin", [(D) Pro]
^3- There is "cyclosporin".

[According to the current conventional nomenclature for cyclosporins, they are defined on the basis of the structure of "cyclosporin" (ie, cyclosporin A). This indicates an amino acid residue that is different (exists) from the amino acid residue that is present in "cyclosporin" (eg, "[(D) Pro]".
³ "indicates that the cyclosporin in question has a-(D) Pro-, rather than a -Sar-residue at the 3-position), and then the term" cyclosporin "is applied to leave the residual cyclosporin present. This is done by showing the characteristics of the remaining residues that are consistent with the group. For individual residues, the residue at position 1-MeBm
Numbering starts from t-, dihydro-MeBmt- or its equivalent residues. ] Furthermore, a great many of these cyclosporins exhibit a medicinal usefulness comparable to that of "cyclosporin" or a more specific usefulness, for example, an activity of canceling tumor resistance to cytostatic therapy in particular, and those as therapeutic agents. Many proposals regarding the applicability of are described in the literature.

Although "cyclosporin" has made a tremendous contribution to the treatment of organ transplantation and autoimmune diseases, in particular, the difficulties encountered in providing a more effective and convenient means of administration,
And the reported occurrence of unwanted side effects, especially nephrotoxic reactions, is a clear and serious obstacle to its widespread use or application.

Cyclosporins are characterized by high hydrophobicity. Liquid formulations proposed for oral administration of, for example, cyclosporins have traditionally been based on the use of oils in combination with a solvent system as carrier medium, for example ethanol and labrafil and equivalent excipients. That is, the commercially available "Cyclosporin" drinking solution uses ethanol and olive oil as carrier media with labrafil as cosolvent (see, for example, U.S. Pat. No. 4,388,307). However, the use of drinking solutions and similar compositions proposed in the art is fraught with a variety of difficulties.

First, the use of oil-based systems has traditionally required the use of high ethanol concentrations to maintain solubility. The use of ethanol is not inherently desirable per se, especially when it is expected to be administered to children. In addition, precipitation appears, for example as a result of the evaporation of ethanol from the encapsulated form or other forms (eg when opened). When these compositions are formulated, for example in the form of gelatine soft capsules, this particular problem makes it necessary to package the product in an airtight compartment, for example an airtight blister or an aluminum foil blister-package or container. is there. As a result, the product is bulky and expensive to manufacture. The storage properties of these formulations are far from ideal.

Also, the use of these dosage forms is characterized by very high variability in the required patient dose. To achieve effective immunosuppressive therapy, cyclosporine blood or serum levels must be maintained within certain limits.
In this case, this range covers the particular condition being treated, e.g. whether the therapy is intended to prevent transplant rejection or control an autoimmune disease or condition, and another immunosuppressive therapy is cyclosporine therapy. It may change depending on whether they are used at the same time. However, empirically,
For example, with the available "Cyclosporine" drinking solution, the daily dose required to achieve the required serum levels varies considerably between individuals and even in single individuals over time. For this reason, monitoring blood / serum levels in patients undergoing cyclosporine therapy at regular and frequent intervals in order to be able to adjust the daily intake to maintain blood / serum levels within the required range. is necessary. Blood / serum level monitoring, which is generally performed using RIA or equivalent immunoassay techniques, such as those based on monoclonal antibodies, must be done on an orderly basis for each patient receiving "cyclosporin" therapy. I have to. This is necessarily time consuming and inconvenient, and adds substantially to the total cost of treatment.

Similarly, blood / serum cyclosporine levels achieved with the available dosing systems exhibit great variability between peak and trough levels. That is, effective cyclosporine blood levels for each patient vary widely between administration of individual doses. It has been found that this variability in patient response can be attributed, to a large extent, to variability in the availability of natural surfactant components such as bile acids and salts in the gastrointestinal tract of the treated subject. Cyclosporine formulations known to date in the art require the presence of a sufficient amount of their natural surfactants to achieve satisfactory absorption. However, the availability of these surfactants in the gastrointestinal tract necessarily varies between subjects and over time in individual subjects.

In addition to the unsatisfactory nature of inconsistency in the above-mentioned treatments, this also ensures that, for example, peak levels are not mistakenly recorded as a high response to a dose, so that it is within a relatively narrow window of time. This means that each patient must be monitored at each time point.

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

There have been several suggestions in the art to solve these various problems, including both solid and liquid oral dosage forms. However, the most serious obstacle is still the insolubility characteristic of cyclosporins, such as "cyclosporin", in aqueous media, thus allowing convenient use and yet meeting the requirements for bioavailability, for example in the stomach or It consists in providing a dose which may comprise cyclosporine in a concentration high enough to enable effective absorption from the intestinal lumen and achieving consistently reasonably high blood / serum levels.

As already mentioned, oral dosage forms of "cyclosporin" which are currently on the market are described, for example, in US Pat.
No. 388307 disclosed and claimed. An early stage of this development is shown in Swiss patent application No. 8634 / 78-8, which is used as a priority certificate for this patent. This application contains the following components: i) sesame oil, ii) nonionic surfactants such as Tween 8
0, Cremophore EL, 40 or 60 or lecithins, iii) transesterified nonionic triglycerides such as Labrafil, iv) lecithin (eg, Epikuron), component (iii)
And ethyl oleate, v) neutral oils such as saturated C _8-12 triglycerides such as Miglyol 812, and vi) mono- and / or di-glycerides such as glycerin monooleate, glycerin mono. The present invention relates to a formulation containing "cyclosporin" as an active ingredient together with a carrier medium containing one or more of stearates and glycerin distearates.

In this specification, including the examples, (i) is described for oral or parenteral administration alone, and (ii)
Are described for use in combination with ethanol for oral or parenteral administration, and with component (v) for parenteral administration, (iii) alone or as a vegetable oil and additional for oral or parenteral administration. Is described for use with ethanol in (iv) for oral administration and for a defined combination with yet another possible additive, such as a preservative, (v)
Is a combination with a solvent such as ethanol, benzoic acid benzyl ester, 1,2-butylene glycol-1-methyl ether and component (iii) (Labrafil) and with the above component (ii), especially for parenteral administration. Described for use, (vi) for oral administration in encapsulated or pellet form, alone or as a thickener,
For example, it is described for use in combination with Aerosil or cellulose. No specific proposal has been made regarding the combination of component (vi) [mono- / di-glycerides] with any of the other components (i)-(vi) and vice versa.

In the patent application completed as U.S. Pat. No. 4,388,307, the focus of development disclosed in the above Swiss application was to focus on components (iii) [Labrafil etc.], (v) [neutral oils] and (vi) [mono- / Di-glycerides, in particular stearic acid or oleic acid mono- / di-glycerides, in particular glycerin monooleate], together with a carrier medium comprising a cyclosporine as an active ingredient. focusing. For oral dosage forms, the use of co-solvents, ethanol and vegetable oils such as olive oil and corn oil is preferred. component
(v) is specifically indicated as preferred for parenteral dosage forms. Component (vi) is proposed for use with lecithins, optionally together with component (iii) in an orally administered aqueous or aqueous / ethanolic emulsion.

[Dihydro-MeBm mainly in the treatment of multiple sclerosis
t] ^1- [Val] ^2- "cyclosporin" (or dihydro-
Belgian patent No. 8 on the use of cyclosporine D)
95724 is also suitable for the administration of this particular compound.
The oral formulation of the species is described. Both of these are based on the commercially available "Cyclosporine" (Sandimun ™) drinking solution, which is tailored to the specific cyclosporin active ingredient. The first formulation was 5-10% [dihydro-MeBmt] ^1- [Val] ^2- "cyclosporin", 10-1.
2% ethanol, 30-40% mycin (Maisin
e), containing about 4% cremophor and 51-30% labrafil (i.e. qs to 100%). This corresponds to the composition of Sandymun ™ drinking solution, with the exception of replacing the natural vegetable oil component with mycin and introducing a small percentage of the surfactant Cremophor. Mycin is a transesterification product of corn oil and glycerin, the more precise composition of which is as follows: It contains about 1: 1 of corn oil derived triglycerides and mono- / di-glycerides.
It is contained in a ratio of 8 ppw (tri-: mono- / di-glycerides). The ratio of cyclosporin: surfactant in the disclosed composition is about 1: 0.4-0.8 and the ratio of cyclosporine: triglycerides: mono- / di-glycerides is about 1: 0.4-0.9: 2.6-7.1. Is. There is no suggestion of a possible increase in surface-active ingredients or any means of avoiding the use of labrafil or ethanol components as cosolvents.

The second disclosed composition comprises 15-25% [dihydro-MeBmt] ^1- [Val] ^2- "cyclosporin", 2-5%.
Ethanol, 40-60% mycin and 10-4
Contains 0% Imwitor 742,> 45% coconut oil mono-glyceride product with monoglycerides and additional di- and tri-glyceride components.
Again, the use of ethanol is unavoidable and no proposals have been made regarding the incorporation of any surface-active ingredients.

Australian Patent Application 87335122 discloses surfactants belonging to the group consisting of polyethoxylated castor oil, polyethoxylated hydrogenated castor oil and polyethoxylated fatty acids derived from castor oil or hydrogenated castor oil,
For example, controlled release systems such as Cremophor, Milji (M) as solubilizers for the introduction of poorly soluble pharmaceutical ingredients into hydrophilic gel systems.
yrj) and Nikkol HCO-60. The sparingly soluble drugs mentioned also include "cyclosporin", but no application of the system to cyclosporin is given. Their solubilizers in combination with single fatty acid mono-, di- or tri-glycerides /
No suggestion is given regarding the use of surfactants.

According to the present invention, surprisingly, for example, cyclosporins, particularly "cyclosporin" active ingredients, which solve or substantially reduce the above-mentioned administration problems faced in the art up to now, are provided. It has been found that the containing pharmaceutical composition can be achieved by the use of a carrier system comprising fatty acid tri-glycerides and mono- / di-glycerides in the form used in combination with hydrophilic surfactants. In particular,
With said carrier system, there is no need for the presence of additional solvents, cosolvents or solubilizers, such as ethanol or labrafil, etc., rather than aqueous emulsions, and known cyclosporine / fatty acid triglycerides / solvents / cosolvent systems such as the known Sandimun. It has been found that it is possible to obtain an oil-based composition that exhibits high stability and improved bioavailability properties compared to the TM drinking solution.
This invention is, in an embodiment, an oil-based pharmaceutical composition, in particular ethanol-free or substantially free,
Pharmaceutical compositions based on oils other than aqueous emulsions are provided.

In particular, the composition according to the invention simultaneously enhances the absorption / bioavailability level and / or the absorption / bioavailability achieved both in individual patients receiving cyclosporine therapy and between individuals. It has been found to allow effective cyclosporine administration with reduced variability in availability levels. In particular, surprisingly, the compositions of the invention have no or substantial dependence on the relative bioavailability of natural surface-active ingredients, such as bile acids or salts, in the gastrointestinal tract of the subject being treated. It has been found to allow absorption of cyclosporine in a chemically reduced form. Applying the mathematical principles of this invention results in a cyclosporine dosage form that reduces the variability in cyclosporine blood / serum levels achieved between doses and between individuals. 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.

More precise standardization of individual patient dose rates and blood / serum level responses, as well as dose and response parameters for patient groups, can reduce monitoring requirements, or substantially reduce treatment costs.

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

Furthermore, the compositions of the present invention exhibit improved stability on storage as compared to compositions based on the use of ethanol or equivalent alkanols, especially by formulating, for example, in the form of capsules, such as gelatine hard or soft capsules. It fits. Compositions according to the discoveries of the invention that are ethanol-free or substantially free of ethanol are characterized by the elimination or substantial reduction of the packaging problems mentioned above, eg with respect to packaging in gelatine soft encapsulation form. Have significant advantages.

According to this invention, in its broadest aspect: (a) cyclosporine as an active ingredient, (b) fatty acid triglyceride, (c) glycerin fatty acid partial ester or propylene glycol (eg, 1,2-propylene glycol) or sorbitol complete or partial ester, and (d) at least 10 Hydrophilic-lipophilic balance (HL
A pharmaceutical composition comprising in a carrier medium comprising a surfactant having B), wherein components (b) and (c) are composed or consist essentially of the individual components of the transesterification product of vegetable oil and glycerin. The composition is (i) ethanol-free or substantially free,
Alternatively, (ii) component (a) is “cyclosporine” or [Nva] ² −
There is provided a composition comprising "cyclosporin" or (iii) 1: containing components (a) and (b) in a proportion of at least 1 ppw.

The above conditions (i) to (iii) are compatible with each other. That is, the present invention includes a composition satisfying any one or more of the above criteria.

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.

Component (a) is suitably present in the compositions of this invention in an amount of about 2-20%, more preferably about 5-15%, based on the total weight including components (a)-(d). To do. Component (a) can be, for example, any therapeutically applicable cyclosporine as indicated above. Preferred components in the composition of the present invention
(a) is "cyclosporin". More preferred component (a) in the composition of the present invention is cyclosporin G
Also known as [Nva] ^2- “cyclosporin”.

Examples of suitable components (d) in the compositions of this invention are as follows.

(d.1) A reaction product of natural or hydrogenated castor oil and ethylene oxide. These products can be prepared in a known manner, for example in West German publications Nos. 1182388 and 15
According to the method disclosed in No. 18819, for example, about 1: 3.
It can be produced in a molar ratio of 5 to about 1:60, for example by reacting natural or hydrogenated castor oil with ethylene oxide and optionally removing the polyethylene glycol component from the product. Particularly suitable are the various surfactants available under the trade name Cremophor. Particularly suitable are saponification numbers of about 50-60, acid numbers <1, iodine numbers <1,
Moisture content (Fisher) <2%, about 1.453-1.457 ▲ n
Cremophor RH40 having ⁶⁰ _D ▼ and HLB of about 14-16, saponification number of about 40-50, acid number <1, iodine number <1, water content (Fisher) 4.5-5.5% and about 1.
Cremophor RH60 having an n ⁶⁰ _{D of} 453-1.457 and an HLB of about 15-17, and a molecular weight of about 1630 (by osmometry), a saponification number of about 65-70,
It is a product such as Cremophor EL having an acid number of about 2, an iodine number of about 28-32 and a n ⁶⁰ _{D of} about 1.471. Also suitable for use in this category are various surfactants available under the trade name Nikkor, such as Nikkor HCO-40 and HCO-60.
The product Nikkor HCO-60 is a reaction product of hydrogenated castor oil and ethylene oxide, and has the following characteristics: acid value of about 0.3, saponification value of about 47.4, hydroxyl value of about 42.5 and pH of about 4.6.
(5%), color APHA = about 40, melting point = about 36.0 ° C.,
Freezing point = about 32.4 ° C., H ₂ O content (%, KF) = 0.03.

(d.2) Polyoxyethylene-sorbitan-fatty acid esters, such as mono- and tri-lauryl, palmityl, stearyl and oleyl esters, such as Tween (reference, Fiedler, "Lexikon der Hilfstofe") , Second Revised and Expanded Edition (1981), Volume 2, 972-975.
Products of the known type marketed under the trade name of page).
For example, the following Tween products. 20 [polyoxyethylene (20) sorbitan monolaurate], 40 [polyoxyethylene (20) sorbitan monopalmitate], 60 [polyoxyethylene (20) sorbitan monostearate], 65 [polyoxyethylene (20) Sorbitan tristearate], 85 [polyoxyethylene (20) sorbitan trioleate], 21 [polyoxyethylene (4) sorbitan monolaurate], 81 [polyoxyethylene (5) sorbitan monooleate], of the present invention Particularly preferred products of this type for use in the composition are the products Tween 40 and Tween 80 described above.
Is.

(d.3) polyoxyethylene fatty acid esters, for example Miruji (reference Fiedler, supra, 1, 228 pages) polyoxyethylene stearic acid esters of the type known commercially available under the trade name. A particularly preferred product of this type for use in the compositions of this invention has a D ²⁵ = about 1.1,
Melting point = about 40-44 ° C, HLB value = about 16.9, acid value = about 0
Millji 52 product having a -1 and a saponification number = about 25-35.

(d.4) For example, Pluronic, Encalyx (Em
kalyx) and Poloxamer (reference, Fiedler, supra, 2 , 720-723), known types of polyoxyethylene-polyoxypropylene copolymers and block copolymers. Particularly preferred products of this type for use in the compositions of this invention have a melting point of about 52 ° C and about 6800-89.
A Pluronic F68 product having a molecular weight of 75.
A further preferred product of this type for use in the compositions of this invention is the Poloxamer 188 product.

(d.5) Dioctyl succinate or di- [2-ethylhexyl] -succinate (reference, Fiedler, supra)
1 , p. 307).

(d.6) Phospholipids, especially lecithins (reference, Fiedler,
Supra, 2 , pp. 559-560). Lecithins suitable for use in the compositions of this invention include soy lecithins, among others.

(d.7) Propylene glycol mono- and di-fatty acid esters such as propylene glycol dicaprylate (also known and commercially available under the tradename Miglyol 840), propylene glycol dilaurate, propylene glycol hydroxy Stearate, propylene glycol isostearate, propylene glycol laurate, propylene glycol ricinoleate, propylene glycol stearate, etc. (reference, Fiedler, supra, 2 , 760 and the next page).

(d.8) Sodium lauryl sulfate.

The ratio of components (a) :( d) in the composition of the present invention is preferably about 1: 1 to 25 ppw, more preferably 1: 1.25.
~ 20 ppw, more preferably 1: 1.5-8 or 10 pp
w, for example about 1: 2-5 ppw. Most preferably, the ratio of components (a) :( d) is 1: at least 2 ppw. That is, the component (a) is preferably a component in the composition of the present invention.
It is present in an amount of, for example, about 20-50% by weight, more preferably 25-40% by weight, based on the total weight of (a) and (d).

As is apparent from the above definition (A), the components (b) and (c) in the composition of the present invention are composed of a single component, such as individual components (b) and (c) of a single material or product. It may be included in, or configured by, or essentially constituted by. Examples of components suitable for use in this invention, including both components (a) and (b), are, for example, known mixed fatty acid tri-glycerides and fatty acid mono- / di-glyceride products. Suitable products of this type include in particular vegetable oils [saturated or unsaturated, including hydrogenation], such as tonsil oil, groundnut oil, palm oil or preferably corn oil and glycerin, propylene glycol (eg,
There are transesterification products with 1,2-propylene glycol) or sorbitol.

These transesterification products are generally transesterified, for example by glycerin decomposition, by heating vegetable oils, such as corn oil, with glycerin, propylene glycol or sorbitol at elevated temperature under continuous stirring, for example in a stainless steel reactor, under an inert atmosphere. , Sugar decomposition or sorbitol decomposition.

Thus, transesterification products suitable for use in accordance with the present invention include mono-, di- and tri-glycerides (i.e., glycerin mono-, di- and tri-esters) and generally small amounts of free glycerin. Including a mixture of.

When the components used in this invention, including both components (b) and (c), are obtained by transesterification of vegetable oils with propylene glycol or sorbitol, they are also
Contains small amounts of free propylene glycol or sorbitol. They are also, for example, in the case of transesterification products with propylene glycol, propylene glycol mono- and di-esters and in the case of transesterification products with sorbitol, sorbitol mono-, di- and tetra-esters. , Containing the esters in significant amounts.

The amount of triglyceride present in the components used in this invention, including both components (b) and (c), is preferably significant, relative to the total weight of [(b) + (c)] in said components. Ratio, eg greater than 5% by weight, preferably 7.5-12% by weight
Or occupy more than that.

The amount of free glycerin + propylene glycol or sorbitol (if present) present in the components used in this invention, including both components (b) and (c), is preferably based on the total weight of said components. Is less than 10%, more preferably less than 5%, most preferably 1-2% or less. The amount of mono-glyceride present in the components used in this invention, including both components (b) or (c), is preferably about 25-50% by weight, more preferably about 25-50% by weight, based on the total weight of said components. It is about 30 to 45% by weight.

When a transesterification product of vegetable oils, such as corn oil and glycerin, is used as the ingredient to give [(b) + (c)], the amount of free glycerin present in said product is preferably less than 10% by weight. , And more preferably 5
Less than 4% by weight, most preferably less than about 4% by weight. The amount of mono-glyceride present is preferably about 30 or 35-50% by weight, more preferably about 35 or 4.
It is 0 to 45% by weight. The amount of di-glyceride present is preferably less than about 60% by weight, suitably 40% by weight.
Is less than. The amount of tri-glyceride present is preferably about 10% by weight, for example about 7.5-14% (all percentages being based on the total weight of the product). That is, the components in the exchange product that is discarded as bait
The ratio of (b) :( c) is preferably about 1: 8 to about 1: 9 ppw.

When the transesterification products of vegetable oils such as corn oil and sorbitol are used as the ingredients to give [(b) + (c)], the free glycerin + present in said products
The amount of free sorbitol is preferably less than 5% by weight, more preferably less than about 1-2% by weight. The amount of mono-glyceride present is preferably about 30-40% by weight, more preferably about 35% by weight. (All percentages are based on the total weight of the product).

Particularly suitable of the above transesterification products suitable for use according to the invention are commercially available, eg under the trademark Mycin. It is a transesterification product of corn oil and glycerin. Their products are mainly composed of linoleic acid and oleic acid mono-, di- and tri-glycerides, containing small amounts of palmitic acid and stearic acid mono-, di- and tri-glycerides together (corn The oil itself is based on about 56% linoleic acid, 30% oleic acid, about 10% palmitic acid and about 3% stearic acid by weight). Physical properties for mycin [36, available from Etabrissmann-Gatufosse Company of 36, Human de Guna, Peau Box 603, 69804 Saint-Priest, Seduc (France)] are indicated by the approximate composition below. .

Free glycerin-up to 10% (typically 3.9-4.9% or even 0.2% in more recent batches) Monoglycerides-about 40% (typically 41-44.1% or even In recent batches, about 38%) Diglycerides-about 40% (or even more recent batches, about 46%) Triglycerides-about 10% (or more recent batches, about 12%) ) Free oleic acid content-about 1%.

Other physical properties for mycin are acid number = maximum about 2, iodine number = about 85-105, saponification number = about 150-175,
Inorganic acid content = 0.

Fatty acid content for mycin is typically about 11% palmitic acid, about 2.5% stearic acid, about 29% oleic acid, about 56% linoleic acid, about 1.5% other acids.
Is.

Further transesterification products mentioned above suitable for use according to the invention are, for example, sorbit glycerides from the company Etablissman Gatufossey.
A transesterification product of corn oil and sorbitol, such as sorbit.
Glyceride WL713, having the following approximate composition:

Product: Transesterification product of about 2 moles corn oil and about 1 mole sorbitol: Rough composition- Monoglycerides-about 35% additional di- and tri-glycerides and sorbitol mono-, di-, tri- and tetra-esters.

Color (Echelle Garner) = <8. Highly soluble in ethanol and chloroform / slightly soluble in ethyl ether / insoluble in H ₂ O. Acid value = <1, Saponification value = about 160-185, Iodine value = about 110-140.

In the composition according to the present invention, components (b) and (c) are
When constituted or essentially composed of individual components (b) and (c) of a single component, for example, components (b) and (c) consist wholly or substantially entirely of said transesterification product. In this case, the ratio of (a): [(b) + (c)] is preferably 1: 0.7.
It is about 5-35, preferably 1: 1-25 ppw, more preferably this ratio is about 1: 3-10, especially about 1: 6 ppw. When only the components containing both (b) and (c) are used, that is, [(b) + (c)] is the total weight of the composition of the present invention including components (a) to (d). On the other hand, it is preferably about 15-70% by weight, more preferably about 20-50.
Present in an amount of% by weight.

From the foregoing, the present invention also provides, in an embodiment, B. A pharmaceutical composition containing a) cyclosporine as active ingredient in a carrier medium consisting of b + c) a vegetable oil and a transesterification product of glycerin, propylene glycol or sorbitol, and d) a surfactant having at least 10 HLB. Where the composition does not contain any of the other components (b) or (c) described in (A) above, i) is ethanol-free or substantially free, or ii) the component ( a) as “cyclosporin” or [Nva] ² −
A composition comprising "cyclosporine" or iii) 1: containing components (a) and (d) in a proportion of at least 1 ppw.

Ingredients in the Composition of the Invention in the Preferred Ratios Above
In order to allow the combination of (b) and (c), the component (b) in the composition of the present invention is preferably the above component (b).
(Ie fatty acid triglycerides) or consist or consist essentially of, eg at least 75% by weight, preferably at least 90%
%, More preferably at least 95% of component (b), at least one component which may be defined as fatty acid triglyceride itself, such as a material or product. Component (c) in the composition of the present invention may also preferably be defined as a glycerin fatty acid partial ester or propylene glycol or sorbitol full or partial ester itself, such as component (c) above, or thereby constituted or essential. Is composed of, for example, at least 75%, preferably at least 90%, more preferably at least 95% by weight of at least one component, which comprises said component (c).

More preferably, the component (b) in the composition of the present invention
And (c) comprises separate components combinable in the selected ratios (b) :( c) described below. That is, component (b) and
With regard to (c), the composition of the invention is most preferably constituted by a bi-partite combination of a component according to definition (b) and a component according to definition (c), for example component (b) or Includes combinations consisting of the first component (s) that consist essentially of it, and the second component (s) that consist or consist essentially of component (c).

Suitable components (b) include both saturated (including hydrogenated) and unsaturated fatty acid tri-glycerides, especially animal or vegetable oils. The fatty acid component of component (b) preferably comprises a saturated or mono-, di- or polyunsaturated acid having a chain length of, for example, 6 to 22 carbon atoms. Particularly suitable for use according to the invention is a high content of unsaturated fatty acid components, especially at least 16 carbon atoms, preferably 18 carbon atoms.
Fatty acid triglycerides having mono-, di- and poly-unsaturated fatty acids having one or more carbon atoms and having a particularly high olein, linole or linolenic fatty acid component content. Of particular interest are fatty acid triglycerides having a linole and / or linolenic acid component content of at least 45%, preferably at least 60% and not more than 65 or 80%, for example when using highly refined oils.

A first group of fatty acid triglycerides suitable for use according to the invention is saturated C _6-12 fatty acid vegetable oil triglycerides,
Examples include capryl-capric acid triglycerides.
That is, examples of suitable components as component (b) include fractionated vegetable oils such as fractionated coconut oil such as Miglyol (Reference, Fiedler, supra, 2 , 615 and 6).
16) Known products marketed under the trade name such as Miglyol 810, ie a molecular weight of about 520 and fatty acid composition = C ₆ max. About 2%, C ₈ about 65-75%, C ₁₀
There are capric triglycerides - about 25-35%, fractionated coconut oil caprylic having C ₁₂ up to about 2%. Miglyol 810 has the following additional physical properties: ▲ α ²⁰ _D ▼ =
1.4490-1.4510, acid value = maximum 0.1, saponification value = about 340-
360, iodine value = having a maximum of 1. Particularly preferred are Miglyol 812, or about 5-0 molecular weight and fatty acid structure = C ₆ up to about 3%, C ₈ about 50-65%,
Fractionated coconut oil capryl-capric triglyceride having a C _{10 of} about 35-40% and a C ₁₂ maximum of about 5%.
Miglyol 812 has the following additional physical properties: ▲ α ²⁰ _D
▼ = 1.4480-1.4500, Saponification number = about 330-345, Iodine number = 1 at maximum.

Further components of a similar type suitable for use as component (b) are the known products marketed under the trade name Estasan, for example Estasan GT8-60 and GT8-65. The Esta Sun GT8-60 is
It is a vegetable oil fatty acid triglyceride whose fatty acid component is mainly composed of saturated C _8-10 fatty acids, especially capryl and capric acid. Fatty acid composition = caproic acid (C ₆ ) up to about 3%,
Caprylic acid (C ₈ ) up to about 50-65%, Capric acid (C ₁₀ )
Up to about 35-45%, lauric acid (C ₁₂ ) up to about 3%. Estasan GT8-60 has the following additional physical properties: Saponification number = about 325-345, Iodine number = up to about 1, Acid number = up to about 0.1, α ²⁰ _D ▼ = about 1.448-1.451. The Esutasan GT8-65 is predominantly saturated C _8-10 fatty acids, vegetable oil fatty acid triglycerides composed of particular caprylic and capric acids. Fatty acid composition = caproic acid maximum about 1%, caprylic acid minimum about 65%, capric acid about 25-3
5%, lauric acid up to about 1%.

Still another ingredient of this type is a known product marketed under the trade name Myritol, for example Millitol 318 [reference, Fiedler, supra, 2 , 635-6.
36 page]. Millitor 318 has a saponification value of about 34
0-350, iodine value = about 0.5 and ▲ n ²⁰ _D ▼ = about 1.44
It is a capryl / capric acid triglyceride having 8-1.450.

Further components suitable for use as component (b) include, for example, vegetable oils such as corn oil, almond oil,
Seed oil (for example, apricot seed oil), avocado oil, babassu oil, higher fatty acid coconut oil, primrose oil, grape seed oil, menhaedon oil, olive oil, orange roughy oil, peanut oil, safflower There are oils, sesame oil, soybean oil and wheat malt oil and animal oils such as fish oils such as fish liver oils such as shark liver oils and mink oils. Refined oil of any of the above types,
In particular, for example, the following contents of olein / linole / linolenic acid components: olein linole Linolene Example acid acid acid about 9% about 68% about 15% evening primrose oil about 27% about 64% -grape seed oil about 4% about 13% Approximately 76% Safflower oil Approximately 5% Approximately 40% Approximately 47% Sesame oil Approximately 25% Approximately 54% Approximately 6% Soybean oil Approximately 14% Approximately 58% Approximately 8% Refined vegetable oils having wheat malt oil are particularly suitable for use according to the invention. Interesting.

Component (c) is preferably a glycerin fatty acid partial ester,
That is, fatty acid mono- or di-glyceride or an acetylated derivative thereof is included. The components suitable for use as component (c) are preferably free of or substantially free of fatty acid triglyceride components, eg the content of fatty acid triglycerides is less than 25%, preferably less than 10%,
More preferably it is less than 5%, for example less than 1 or 2%.

Suitable components (c) for use in the compositions of this invention include
Symmetrical mono- and di-glycerides (ie β-monoglycerides and α, α ¹ -glycerides) and asymmetrical mono- and di-glycerides (ie α-
Both monoglycerides and α, β-diglycerides) and their acetylated derivatives. They also include both homogeneous glycerides (ie the fatty acid component is mainly composed of a single fatty acid) as well as mixed glycerides (ie the fatty acid component is composed of various fatty acids) and their acetylated derivatives. including.

The fatty acid component of component (c) may include both saturated and unsaturated fatty acids having a chain length of 6 to 22 carbon atoms. Preferably, the fatty acid component is predominantly 8 to 18 carbon atoms, especially 8, 10 or 14 to 18, for example 16
And saturated or unsaturated fatty acids having a chain length of 8 or 18 carbon atoms. Particularly suitable are mono- and di- whose fatty acid component is mainly composed of one or more members selected from the group consisting of caprylic acid, capric acid, linolenic acid, palmitic acid, stearic acid and oleic acid. -Glycerides.

Particularly preferred for use as component (c) are mono- and di-glycerides having a mono- / di-glyceride content of at least 50% by weight, preferably at least 60% by weight, more preferably at least 75% by weight. It is a component containing a class and acetylated derivatives thereof. component
Examples of suitable components for use as (c) are as follows.

(c.1) Invitor (reference, Fiedler, supra,
1 , page 491) fatty acid mono- and di-glycerides, in particular capryl and capric acid mono- and di-glycerides, such as invitol 742, which has at least 45% of said mono-.
Containing glycerides, the following additional characteristic data: Acid value = maximum about 2%, iodine value = maximum about 1.0, saponification value = about 250-2
80, free glycerin content = maximum about 2%),
And stearic acid mono-glycerides, such as Invitol 191 (which contains at least 90% of said mono-glycerides, the following additional characteristic data: mp = about 6).
3-66 ° C, acid value = maximum about 3, saponification value = about 160-17
0, iodine value = maximum of about 3, free glycerin content = maximum of about 2%), and invitol 960K, which contains 30-40% of the monoglycerides, with the following additional characteristic data: mp = about 56 to about 60 ° C., saponification value = about 155-170, acid value = maximum about 3, iodine value = maximum about 3, and free glycerin content = maximum about 4%).

(c.2) Cutina (reference, Fiedler, supra,
1 , 263 and 264) commercially available fatty acid mono- and di-glycerides, especially palmitine and stearic acid mono- and di-glycerides, such as the aforementioned mono- and di-glycerides, The following characteristic data: Acid value = maximum about 8, saponification value = about 16
Including cutina MD-A exhibiting 0-170, and stearic acid mono-glycerides such as the aforementioned mono-glycerides, the following characteristic data: mp = about 54-60 ° C., acid value = about 2, saponification value. = About 162-173, iodine value =
Cutina GMS with a maximum of about 2.

(c.3) Fatty acid mono-glycerides marketed under the trade name Myverol (Reference, Fiedler, supra, 2 , 637), especially C ₁₈ fatty acids such as linolenic acid, mono-glycerides such as Mibelol 18-9
2. It contains at least 90% of said mono-glycerides and exhibits the following additional characteristic data: acid number = maximum about 3.0, diglyceride content = maximum about 5%, free glycerin content = maximum about 1.2%.

(c.4) Fatty acid mono-glycerides, especially stearic acid mono-glycerides commercially available under the trade name Myvaplex (reference, Fiedler, supra, 2 , 637), such as Mibaplex 600 series. Product, eg containing about 94-90% of said mono-glycerides, the following additional characteristic data: mp = about 73 ° C., density = 80
Mivaplex 600P that exhibits about 0.92 g / cm ³ at ℃.

(c.5) Fatty acid mono-glycerides commercially available under the trade name Estagel, eg mainly C _16-18
Estagel G-18 composed of fatty acid mono-glycerides, especially palmitin and stearic acid mono-glycerides. The α-monoglyceride content of Estagel G-18 is a minimum of about 40%. Other characteristic data: acid value = maximum about 2, saponification value = about 162-173, iodine value = maximum about 3, free glycerin content = maximum about 6%.

(c.6) For example, acetylated fatty acid mono- and di-glycerides, especially mono- and di-, commercially available under the trade name Myvaset (reference, Fiedler, supra, 2 , pp. 636-637). Acetylated fatty acid mono-glycerides such as mono- and di-acetylated stearic acid mono-glycerides such as the following characteristic data:
Mivaset 9-40 having α ⁵⁰ _D ▼ = about 1.4468-1.4476, mp = about 5 ° C., acid value = maximum about 1.5, saponification value = about 375-385 and the following characteristic data: ▲ α ⁵⁰ _D ▼ = about 1.4465
-1.4475, mp = about 8-12.4 ° C, acid value = about 1.5, saponification value =
Mivaset 9-45 with about 375-385.

Still another particularly useful component (c) is mixed glycerin fatty acid partial esters and propylene glycol full and partial esters such as fatty acid mono- and di-glycerides and propylene glycol fatty acid mono- and di-glycerides.
A product containing an ester. Examples of those components (c) include:

(c.7) Atmos [Reference, Fiedler, supra,
1 , page 156], fatty acid mono- and di-glycerides / propylene glycol fatty acid mono- and di-esters, especially Atmos 30 whose fatty acid part is mainly constituted by oleic acid residues.
0, and Atmos 150 whose fatty acid moieties are predominantly composed of stearic acid residues.

(c.8) Fatty acid mono- and di-glycerides / propylene glycol fatty acid mono- and di-esters commercially available under the trade name Arlacel [reference, Fiedler, supra, 1 , pp. 143-144], In particular, Arlacel 186 in which the fatty acid moieties are predominantly composed of oleic acid residues.

Components (b) and (c) are preferably present in the compositions of this invention in a proportion of about 1: 0.02-3.0 ppw. More preferably, the ratio of components (b) :( c) is about 1: 0.1 to 2.5 ppw, most preferably about 1: 0.25-1.25 ppw. If components (b) and (c) in the composition according to the invention comprise eg the separate components mentioned above, said components are preferably used in the same relative proportions. That is, the components in the composition of the present invention
The amount of (b) is suitably 10-50% by weight, preferably 20-40% by weight, based on the total weight including components (a) to (d).
The amount of the component (c) in the composition of the present invention is preferably 1 with respect to the total weight including the components (a) to (d).
The amount is -30% by weight, preferably about 10-25% by weight.

The ratio of (a) :( b) + (c) in the composition of the present invention is preferably about 1: 0.5-40 ppw. Preferably,
The ratio of (a) :( b) + (c) is about 1: 1 to 35, more preferably about 1: 1.5 to 30 ppw, most preferably about 1: 2.
It is 6.

From the foregoing, the present invention also provides C) a pharmaceutical composition according to item A above, which comprises at least one component which is or essentially consists of the component (s) according to item (b) above. , D) A pharmaceutical composition according to paragraph A above, comprising at least one component which is or essentially consists of the component (s) according to paragraph (c) above, and E) components (a) and ( A pharmaceutical composition according to paragraph A above wherein b) comprises separate components.

The compositions of this invention may optionally contain further ingredients such as thickeners, granulating agents, dispersing agents, flavoring and / or coloring agents or antibacterial agents and the like. They may also contain a polymeric thickening agent to allow processing into solid or semi-solid masses suitable for tableting or granulation.

The compositions of this invention are preferably antioxidants for improving shelf life, such as butyl-hydroxy-toluene (or BHT), butyl-hydroxy-anisole (or BHA), ascorbyl palmitate, ascorbic acid, citric acid. Acid or α-tocopherol-acetate.

In particular, the compositions of this invention preferably include one or more stabilizers or buffers to prevent degradation of component (a) during processing or storage, for example. The stabilizers may include acidic stabilizers such as citric acid, acetic acid, tartaric acid or fumaric acid and basic stabilizers such as potassium hydrogen phosphate, glycine, lysine, arginine or tris (hydroxymethyl) aminomethane.

The stabilizers or buffers are suitably added in an amount sufficient to achieve or maintain a pH in the range of about 5-7, more preferably 6-7.

When the components (b) and (c) in the composition of the present invention are constituted by a single component which is a transesterification product of vegetable oil and glycerin, the composition of the present invention is preferably the above (A) item. Subject to condition (i), i.e. they are ethanol-free or substantially free.
More preferably, they are free or substantially free of diluent or another component used as a solvent medium for component (a).

When the condition (i) above applies in particular cases, it is generally preferred that the composition according to the invention is free of ethanol or substantially free of ethanol. It is also generally preferred if the composition according to the invention is free of or substantially free of diluents or other components used as solvent medium for (a). That is, in yet another series of embodiments, the invention also includes F) ethanol-free or substantially free of,
(A) to (E), and (G) a diluent or another component used as a solvent medium for the component (a), which does not contain any or substantially, the above (A)
The pharmaceutical composition according to any one of (1) to (E) is provided.

The composition preferably contains less than 2% by weight, more preferably 0-0.5 or 1% by weight of ethanol, based on the total weight of all components. The composition is suitably less than 20% by weight, more preferably less than 10% by weight, for example 0 to
It contains 2.5 or 5.0% by weight of diluent or further components used as solvent medium for component (a). A particular composition according to the invention consists or essentially consists of components (b), (c) and (d) as a carrier medium for (a), i.e. with the exception of a thickener,
Any of the above (A) to (G), wherein a granulating agent, dispersant, fragrance, colorant, stabilizer or similar excipient may also be present and is present as an additive to the carrier medium. It is the described pharmaceutical composition.

Ingredients used as diluents are to be understood as especially those which aid in reducing the viscosity / increasing the fluidity of the compositions according to the invention. A component used as a solvent medium for (a) should be understood to be a co-solvent or other substance that enhances the solubility of component (a) in the composition of the present invention. Examples of those components are in particular the solvent or diluent components having an HLB of less than 10, eg the transesterification products of natural vegetable oil triglycerides and polyalkylene polyols, eg the trademark Labrafil (reference, Fiedler, supra, 2 , 539). Known products and ethanol marketed under the name.

The composition according to the invention is in a dosage form suitable for administration by any suitable means, for example in the form of creams, gels for topical or ocular administration or granules for oral administration,
It may be applied in the form of tablets, capsules or the like or in a form suitable for intralesional application eg in the treatment of psoriasis. However, preferably the compositions of this invention are administered orally. Therefore, in a preferred embodiment, the present invention provides
There is provided said composition in a form suitable or adapted for oral administration, especially in oral unit dose form. Unit dosage forms that are particularly suitable for oral administration include encapsulated forms, such as gelatine soft or hard encapsulated forms.

Oral unit dose forms according to the invention are for example 2-5 daily
For single administration, it is suitably 5-200 mg, more preferably 20-100 mg, eg about 25, 50 or 10.
Contains 0 mg of component (a).

In addition to the above, the present invention also provides a process for the preparation of a pharmaceutical composition as defined and described above, wherein the components (a), (b), (c) and (d) are intimately mixed. A method including:

In a preferred embodiment, the present invention provides the method as described above, wherein component (a) is composed of or consists essentially of one or more fatty acid triglycerides.
(b), and a second component (c) containing glycerin fatty acid partial ester or propylene glycol or sorbitol complete or partial ester, or a first component (b) containing fatty acid triglyceride, and one or more glycerin fatty acid partial ester And / or a second component (c) composed or essentially composed of propylene glycol and / or sorbitol full or partial ester, and (d) intimately with a surfactant having a hydrophilic-lipophilic balance of at least 10. A method comprising mixing is provided.

In a further preferred embodiment, the present invention is the above method, wherein component (a) comprises a first component (b) consisting or essentially consisting of one or more fatty acid triglycerides, one or more Second component (c) and (d) comprising a glycerin fatty acid partial ester and / or propylene glycol and / or sorbitol full or partial ester of at least 10 having a hydrophilic-lipophilic balance A method comprising intimate mixing with the agent is provided.

[Examples] Hereinafter, the method for producing the composition according to the present invention will be described with reference to Examples.

Example 1 Component Amount (mg) a) Cyclosporine (eg, “cyclosporin”) 50.00 b) Miglyol 812 100.00 c) Mibelol 18-92 100.00 d) Cremophor RH40 50.00 (a)-( Intimately mix d) in the indicated proportions by standard methods,
The mixture obtained is loaded into gelatine soft or hard capsules, each containing 50 mg of cyclosporine.

Example 2 Similar to Example 1, gelatin soft or hard capsules are prepared, each containing the indicated amounts of the following ingredients:

Ingredient Amount (mg) 2aa) Cyclosporine (eg, “Cyclosporin”) 50.00 b) Miglyol 812 100.00 c) Invitol 742 100.00 d) Cremophor RH40 100.00 2ba) Cyclosporine (eg, “Cyclosporin”) 50.00 b) + c) mycin 300.00 d) cremophor RH40 100.00 2 ca) cyclosporine (eg, “cyclosporin”) 50.00 b) soybean oil 150.00 c) mibelol 18-92 50.00 d) emrudine R040 * 250.00 2da) Cyclosporine (eg, “Cyclosporin”) 50.00 b) Sesame oil 150.00 c) Invitol 900K 125.00 d) Emulfo EL-719 * 150.00 2ea) Cyclosporine (eg, “Cyclosporine”) )) 50.00 b) Miritor 318 75.00 c) d Tagel G-18 100.00 d) Pluronic F68 175.00 2fa) Cyclosporine (eg, "cyclosporin") 50.00 b) Estasan GT8-60 130.00 c) Alarcel 186 75.00 d) Tween 80 125.00 2ga) cyclosporine (eg, “cyclosporin”) 50.00 b) + c) mycin 100.00 c) miberol 18-92 200.00 d) Cremophor RH40 100.00 2ha) cyclosporine (eg, “cyclosporin”) 50.00 b) Miglyol 812 100.00 c) Mibelol 18-92 200.00 d) Cremophor RH40 100.00 [* Reference, Fiedler, supra, 1 , 344] The compositions obtained according to Examples 1 and 2 are: Administration in the prevention of transplant rejection or treatment of autoimmune diseases, eg It is suitable for administration daily 1-5 capsule. Equivalent compositions have the same or equivalent amounts of other cyclosporins, such as [Nva] ² −, instead of “cyclosporin” as component (a).
It can be produced by using "cyclosporin".

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 the invention in dogs A group of 8 Beagle dogs (male, approximately 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 is administered by gavage and then Na
20 ml of 0.9% Cl solution is administered. Three hours after administration of test composition, animals are allowed free access to food and water.

A 2m blood sample (or 5m in the blank) was taken from the saphenous vein and -15 minutes (blank) for administration, 30
After minutes, and 1, 1.5, 2, 3, 4, 6, 8, 12 and 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. The analysis of the amount of dispersion is performed by AUC (area under the curve), Cmax (maximum concentration) and Tm
Performed on ax (maximum time).

Average AUC (ng · h / m) calculated from individual test course
^-1 ) and Cmax (ng / m ^-1 ) values as well as the calculated variability (CV) in the response between test animals administered the same test composition is, for example, known sandymun administered at the same "cyclosporin" dose level. Compared to the results in the case of the drinking solution, the composition according to the invention, for example the composition according to Example 1, has a high bioavailability (AUC and Cmax) is proved.

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. Test group is preferably 12
It is composed of objects.

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 within, history of drug or alcohol dependence, blood loss of 500 m or more within the last 3 months,
Drug side effects or hypersensitivity, history of allergies requiring drug treatment, hepatitis B / HIV positive.

A complete physical examination and ECG will be performed before and after the test. The following parameters are evaluated within 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, SGP
T, -GT, alkaline phosphatase, total bilirubin, α-amylase.

Urine-pH, microalbumin, glucose, red blood cells, ketone bodies, precipitates.

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 recognized). 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, 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 cyclosporin measurement were collected in 2 EDTA-coated polystyrene tubes (1 m each) at each time point,
After gently stirring, freeze immediately at -20 ° C. Cyclosporin in whole blood is measured using RIA with 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, in gelatin soft capsule form,
Final weight of contents = 463 mg / dose), compared to the standard, in the case of the composition of Example 1, as reflected in both the established AUC (0-32 hours) and Cmax values. Significant increases in bioavailability levels have been recorded. Furthermore, comparing the change in whole blood "cyclosporin" concentration (measured by specific monoclonal RIA) over time after a single administration of the test composition (150 mg "cyclosporin" dose), all subjects treated with the standard composition It is demonstrated that the variability in the 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 composition described in Example 2.

The present invention enables the following items.

(1) (a) cyclosporine as an active ingredient, (b) fatty acid triglyceride, (c) glycerin fatty acid partial ester or propylene glycol or sorbitol complete or partial ester,
And (d) a pharmaceutical composition comprised in a carrier medium comprising a surfactant having at least 10 HLB, wherein components (b) and (c) are constituted by the individual components of the transesterification product of vegetable oil and glycerin. Or, if essentially constituted, the composition is (i) ethanol-free or substantially free,
Alternatively, (ii) component (a) is “cyclosporine” or [Nva] ² −
A composition comprising "cyclosporin" or (iii) 1: containing components (a) and (d) in a ratio of at least 1 ppw.

(2) (a) is approximately 2 to 2 based on the total weight including components (a) to (d).
The composition of 1, wherein the composition is present in an amount of about 20% by weight.

(3) (d) is a reaction product of natural or hydrogenated castor oil and ethylene oxide, polyoxyethylene-sorbitan-fatty acid ester, polyoxyethylene fatty acid ester, polyoxyethylene-polyoxypropylene copolymer or block copolymer, dioctyls. A composition according to claim 1 or 2, comprising cuccinate, di- [2-ethylhexyl] -succinate, phospholipids, propylene glycol mono- or di-fatty acid esters or sodium lauryl sulphate.

(4) The composition according to any one of 1 to 3, wherein (a) and (d) are present in a ratio of about 1: 1 to 25 ppw [(a) :( d)].

(5) Component (a), component (d) and [(b) + (c)] described in 1.
1 to 4 containing a vegetable oil and a transesterification product of glycerin, propylene glycol or sorbitol
The composition according to any one of 1.

(6) 1 to 4 in which (b) and (c) consist or consist essentially of the individual components (b) and (c) of component [(b) + (c)] according to 6. The composition according to claim 1.

(7) (a) and [(b) + (c)] are about 1: 0.75-35ppw
7. The composition according to 6, which is present in a ratio of [(a): [(b) + (c)]].

(8) 1 to 5 containing at least one component which is or essentially consists of component (b) (which may be more than one) as described in 1 and component (c) (which may be more than one) as described in 1. The composition according to any one of 1.

(9) The composition according to any one of 1 to 6 or 8, wherein (c) contains a glycerin fatty acid partial ester or an acetylated derivative thereof.

(10) (b) and (c) are about 1: 0.02-3.0ppw [(b) :( c)]
The composition according to any one of 1 to 5, 8 or 9, which is present in the ratio of.

Claims (1)

[Claims] 1. A cyclosporine as an active ingredient, (b) a fatty acid triglyceride, (c) a glycerin fatty acid partial ester or propylene glycol or sorbitol complete or partial ester,
And (d) a pharmaceutical composition comprised in a carrier medium comprising a surfactant having at least 10 HLB, wherein components (b) and (c) are constituted by the individual components of the transesterification product of vegetable oil and glycerin. Or, if essentially constituted, the composition is (i) ethanol-free or substantially free,
Alternatively, (ii) "cyclosporine" or [Nv as the component (a)]
a] ^2- "Cyclosporin" or (iii) 1: containing at least 1 ppw of components (a) and (d).