FR2643262A1 - PHARMACEUTICAL COMPOSITIONS BASED ON CYCLOSPORINS - Google Patents

Abstract

The present invention relates to pharmaceutical compositions comprising a cyclosporin as active substance, a fatty acid triglyceride, a partial fatty acid ester with glycerol or a partial or total ester of fatty acids with sorbitol or propylene glycol and a surfactant having an HLB value of at least 10.

Description

The present invention relates to novel galenic formulations

including a

  cyclosporine as active substance.

  Cyclosporins are a class of cyclic poly-N-methyl cyclic undecapeptides with characteristic structure and pharmacological activity.

  in particular immunosuppressive, anti-

  inflammatory and / or anti-parasitic. The first cyclosporin to be isolated is a metabolite

  Fungal of natural origin Ciclosporin or Cyclos-

  porin, also known as cyclosporin A and

  commercially available under the trademark SANDIMMUN R or SANDIMMUNE R. Ciclosporine is cyclosporine of formula A 23 4 5 6 7 8 9 10 i1 (A)

  in which -Me3mt- means a N-methyl- (4R) -

  4-but-2E-en-1-yl-4-methyl- (L) threonyl of formula B CH3: 1 i CH 2

HO (R) CH

CH (R) CH, (B)

-N-CH-CO-

I (S) CH]

  in which -x-y- means -CH-CH- (transi.

  As a parent molecule of the class, Ciclosccrine has been the subject of the greatest attention so far. The main field of clinical investigation for Ciclosporin has been as an immunosuppressive agent, particularly in connection with its use in organ transplant recipients,

  for example, transplants of heart, lung, heart

  lung, liver, kidneys, pancreas, bone marrow, skin and cornea, especially organ transplants. In this sector, Ciclosporin has achieved remarkable success and has

has an excellent reputation.

  At the same time, we sought

  intensive possibilities of application of the Ciclos-

  porin to various autoimmune diseases and inflammatory conditions, particularly inflammatory conditions

  having an etiology comprising an auto-component

  immunity, such as arthritis (eg rheumatoid arthritis, progressive rheumatoid arthritis and deforming arthritis) and rheumatic diseases, and reports of the results of these in vitro, animal and clinical trials are largely

  widespread in the literature. As auto diseases

  specific immune systems for which Ciclosporin has been proposed or used, mention may be made of autoimmune hematological disorders (including, for example, hemolytic anemia, aplastic anemia, anemia

  pure erythrocyte and idiopathic thrombocytopenia

  the systemic lupus erythematosus, the poly-

  chondritis, scleroderma, granulomatosis of

  wegener, dermatomyositis, chronic active hepatitis

  that, myasthenia gravis, psoriasis,

  Steven-Johnson, idiopathic sprue, inflammatory

  intestinal autoimmune disorders (including, for example,

  ulcerative colitis and Crohn's disease), ophthalmic

  endocrine mopathy, Graves' disease, sarcoido-

  se, multiple sclerosis, primary biliary cirrhosis, juvenile diabetes (diabetes mellitus type

  uveitis (anterior and posterior), conjunc-

  spring tivitis, keratoconjunctivitis sicca,

  Interstitial pulmonary fibrosis, psoriatic arthritis

  that and glomeculonephritis (with or without

  nephrotic, for example, including the nephrotic syndrome

  idiopathic tick or low-grade nephropathy

  ments). Other areas of research include the possibilities of using Ciclosporin as an anti-parasitic agent, especially as an anti-protozoan agent, especially for the possible use in the treatment of malaria, coccidiomycosis and schistosomiasis , and more recently to suppress the resistance of tumors to

anti-neoplastic agents etc.

  Since the discovery of Ciclosporin,

  isolated and identified a wide variety of cyclosporins

  of natural origin and many other unnatural cyclosporins have been prepared by total synthesis.

  or chemical modification or by application of

  of modified crops. This class consisting of cyclosporins is now important and includes,

  for example cyclosporins A to Z of natural origin

  [see Traber et al. Helv. Chim. Acta. 60, 1247-1255 (1977); Traber et al. 2, Helv. Chim. Acta, 1655-1667 (1982); Kobel et al., Europ. J. Applied Microbiology and Biotechnology 14, 273-340 (1982); and von wartburg et al., Progress in Allergy, 38, 28-45 (1986)] as well as various unnatural derivatives of cyclosporins and artificial and synthetic cyclosporins, including dihydro-cyclosporins.

  [in which the remainder -x-y- of the remainder -MeBmt-

  (Formula B above) is saturated to give -xy- = -CC H-CH, 2-branching cyclosporines (eg in which another substituent is introduced on the carbon atom c of the sarcosyl residue in position 3 of the cyclosporin molecule), cyclosporins in which the residue -MeBmt- is present in isomeric form (for example in which the

  configuration at positions 6 'and 7' of the remainder -MeBmt-

  is cis instead of trans), and cyclosporins in which various amino acids are incorporated at specific positions in the peptide sequence, using for example the total synthesis method for the preparation of cyclosporins, developed

  by R. Wenger - see for example Traber 1, Traber 2 and-

  Kobel Loc. cit .; U.S. Patent Nos. 4,108,985, 4,210,581 and 4,220,641; European Patent Applications Nos. 34,567 and 56,782; international demand

  86/02080; Wenger 1, Transp. Proc. 15, Suppl.

  1: 2230 (1983); Wenger 2, Angew. Chem. Int. Ed., 77 (1985); and Wenger 3, Progress in the Chemistry of

  Organic Naturals Products 50, 123 (1986).

  The class consisting of cyclosporins is thus very large and includes, for example, the

  [Thr] 2-. [Val] 2-, [Nva] 2- and [Nval2- [Nva] 5-Ciclospo-

  rine (also known as cyclosporin

  C, D, G and M), [3-O-acyl-MeBmt] -cyclosporine (also known as cyclosporin A acetate), [Dihydro-MeBmtll- [Vall2-Ciclosporin (also known

  as dihydrocyclosporin D), [(D) Fluoromethyl-

  Sar] 3-Ciclosporin, [(D) Ser] - Ciclosporin, [MeIlejll-Ciclosporin, [(D) MeVal] II-Ciclosporin (also

  known as cyclosporin H), EMeAla] 6-Ciclosporin, the [(D) Pro] J-

  Ciciosporin, [3'-deoxy-3'-oxo-MeBmt1 EVal] 2- and - [Nva] 2-

Ciclosporin, etc ...

  [In accordance with the nomenclature adopted for cyclo-

  porins, the latter are defined by reference to the structure of Ciclosporin (that is to say Cyclosporin A). According to this nomenclature, the amino acid residues present which are different from those present in Ciclosporin (eg "(D) Pro] 3" are indicated to indicate that the cyclosporin in question has a residue -fD). instead of a remainder -Sar in position 3) and we attach the

  "Ciclosporin" to characterize the other remains that are

  to those present in Ciclosporin. The individual remains are numbered from the rest -MeBmt-, -dihydro-MeBmt- or its

equivalent in position 1l].

  Many of these other cyclosporins have pharmacological activity comparable to that of Ciclosporin or a more specific activity, particularly for the treatment of tumors resistant to cytostatic treatment, and the literature presents various proposals for their use.

therapeutic application.

  Despite the very important contribution in therapy of Ciclosporin, especially in the field of organ transplants and. the treatment of autoimmune diseases, the difficulties encountered in finding a more effective and practical mode of administration and the existence of side effects

  adverse reactions, in particular nephrotoxic reactions

  have seriously limited a wider application of

  product. Cyclosporins are highly hydrophobic. The proposed liquid formulations,

  intended for example for the administration of cyclo-

  oral porins, are therefore essentially based on ethanol and oils or similar excipients used as vehicles. Thus, commercially available ciclosporin oral solution comprises ethanol and olive oil as excipients in combination with Labrafil as surfactant (see U.S. Patent No. 4,388,307). The use of oral solute and similar compositions as proposed in the literature, however, is not

free of difficulties.

  First, the need to use oil-based systems has required the use of high concentrations of ethanol to maintain solubility. The use of ethanol is in itself undesirable, particularly when considering administration to children. In addition, the evaporation of ethanol, for example capsules or other forms, for example when opening the package containing the capsules, causes the formation of a

  cyclosporine precipitate. Where such

  For example, in the form of soft capsules, this particular difficulty involves packaging the encapsulated product in a compartment.

  airtight, for example in mono-

  honeycomb airtight or in mono-

  alveolar aluminum foil. This in turn makes the product both bulky and its preparation expensive. The storage characteristics of such

  formulations are therefore far from ideal.

  The use of such forms of administration

  It is also characterized by extreme variation in the doses to be administered to patients. For effective immunosuppressive therapy, it is important to maintain cyclosporine levels in the blood

  and / or in serum within a specific range.

  The required interval may, in turn, vary according to the particular conditions to be treated, for example if it is a treatment intended to avoid the rejection of a transplant or to treat an autoimmune disease, and if another treatment immunosuppressant is used or

  not at the same time as treatment with cyclosporine

  rine. Experience has shown that using, for example

  the oral solution of Ciclosporin, the daily doses of

  necessary to achieve the required levels in the blood serum, can vary considerably from one individual to another and even for a single individual. This therefore requires regular monitoring of the levels in the blood and / or blood serum of cyclosporine-treated patients in order to adjust the daily dose and administer values that maintain these levels in the meantime. longed for. This control is usually performed by RIA or equivalent radioimmunoassay technique, for example using monoclonal antibodies, and should be performed regularly, which inevitably takes time, is not practical

  and greatly increases the total cost of treatment.

  It also happens that the rates of cyclo-

  porin obtained in the blood and / or serum with the available administration forms show extreme variations between the maximum rate and the minimum rate. This means that for each patient, the effective levels of cyclosporine in the blood vary

  between each dose administration strongly

  ual. This variation in the patient's response is due to variations in the amounts of surfactants of natural origin, for example acids and bile salts, present in the gastrointestinal tract.

  of the treated patient. For commercial galenic forms

  cyclosporins, the presence of such surfactants

  natural assets in sufficient quantity is necessary

  when one wants to obtain a satisfactory resorption.

  However, the amount of such surfactants in the gastrointestinal tract inevitably varies from patient to patient and from patient to patient.

various periods of treatment.

  Apart from the inconvenience of this instability in treatment, it also means that patients must be checked regularly to make sure that the peak is not recorded by the patient.

  error as a high response to the administered dose.

  Besides these obvious practical difficulties, remains the appearance of undesirable side effects already mentioned, which is observed when using

  forms available for oral administration.

  To overcome these difficulties, various

  proposals have been made in the technique

  solid and liquid forms to be administered orally. One of the major difficulties, however, remains the insolubility of cyclosporins, for example Ciclosporin, in aqueous media and therefore the development of a form that may contain cyclosporins in a sufficiently high concentration to facilitate their use and thus meet the criteria of

  bioavailability, for example to allow a

  effective sorption from the stomach or

  testin and to get constant and high rates

in the blood and / or serum.

  As mentioned above, the commercial forms

  The initial phase of this development is described in Swiss Patent Application No. 8634 / 78-8, which serves as a priority document for this patent. . This application relates to galenic formulations comprising Ciclosporin as an active substance together with a vehicle comprising one or more of the following components: i) sesame oil, ii) a nonionic surfactant, for example Tween, Cremophore EL , 40 or 60 or lecithins, iii) a transesterified nonionic triglyceride, for example Labrafil, iv) a mixture of lecithin (eg Epikuron), and ingredient (iii) or ethyl oleate,

  (v) neutral oils, eg triglycerides

  saturated C8-Cl2 wrinkles such as Miglyol 812, and

  vi) mono- and / or di-glycerides such as mono-

  oleate, mono-stearate and glycerol distearate. In the text and examples, (i) is described for use alone, for oral or parenteral administration; (ii) is described for use in combination with ethanol, for oral or parenteral administration, and

  combination with the components (v) for the administration

  parenteral treatment; (iii) is disclosed for use alone and in combination with a vegetable oil and also with ethanol for oral or parenteral administration; (iv) is described in terms of defined combination with other possible additives, for example preservatives, for oral administration; (v) is described for use in combination with solvents such as ethanol, benzyl benzoate,

  1,2-butylene glycol 1-methyl ether and the

  (iii) (Labrafil) as well as in combination with component (ii) described above, in particular for parenteral administration; and (vi) is disclosed for use alone or in combination with thickeners such as aerosil or cellulose

  for oral administration in encapsulated form.

  sulate or micro-granules. No proposal has been made for the combination of components (vi)

  [mono- / di-glycerides] with any of the

sants (i) to (vi), or vice versa.

  In US Pat. No. 4,388,307, the development phase indicated in the aforementioned Swiss patent application is concentrated on compositions comprising cyclosporins such as

  active substances, together with a vehicle com-

  one or more components (iii) [Labrafils

  etc ... l, (v) [neutral oils] and (vi) [mono- / di-gly-

  cerides, especially the mono- / diglycerides of

  stearic or oleic acid, especially mono-

  glycerol oleate]. The use of co-solvents, ethanol and vegetable oils such as olive oil and corn oil is preferred for oral forms. Components (v) are especially preferred for forms to be administered parenterally. Components (vi) are proposed

  for use with lecithins, possibly

  together with component (iii) in

  aqueous or aqueous / ethanolic emulsions

to be oral.

  The Belgian patent born. 895 72-4, which concerns

  essentially the use of [dihydro-MeBmtll-

  [Val] 2-Ciclosporin (or dihydro-cyclosporin D) for the treatment of multiple sclerosis also describes two formulations suitable for oral administration of this particular compound. said

  formulations are based on the oral solution of Ciclospo

  (Sandimmun R), adapted to cyclosporine

  particular rine used as the active substance. The

  first formulation comprises 5-10% of [Dihydro-

  MeBmtll- [Val] 2-Ciclosporin, 10-12% ethanol, 30-40% Maisine, about 4% Cremophore and 30-51% Labrafil (i.e., up to 100%) . This corresponds to the composition of Sandimmun's oral solution, but with substitution of the natural vegetable oil with Maisine and introduction of a small percentage of Cremophore surfactant. Maisine is a transesterification product of corn oil with glycerol comprising triglycerides derived from corn oil and mono- / di-glycerides in a weight ratio of about 1: 8 (triglycerides: mono- / di-glycerides). The weight ratio of cyclosporin to surfactant in said composition is about 1: 0.40, and the

  weight ratio cyclosporine: triglycerides: mono- / di-

  glycerides is about 1: 0.4-0.9: 2.6-7.1. The document does not suggest an increase in the amount of surfactant or any means of avoiding

  the use of Labrafil or ethanol as co-sol

  solvents. The second formulation described in this document

  comprises 15-25% of [Dihydro-MeBmt] l- [Val] 2-Ciclospo-

  10-40% of ethanol, 40-60% of Maisine and 10-40% of Imwitor 742, a monoglyceride of coconut oil comprising more than 45% of monoglycerides with other di- and tri- glycerides. Again, no proposal is made to eliminate the use of ethanol and

to incorporate a surfactant.

  Australian Patent Application No. 87,335,122 discloses the use of surfactants including polyethoxylated castor oils, castor oils

  hydrogenated polyethoxylates and polyethoxylated fatty acids

  xylés derived from castor oil or hydrogenated castor oil, such as Cremophores, Myrj and

  Nikkol HCO-60, as solubilizers for the incorporation of

  use of poorly soluble pharmaceutical agents in controlled release systems, for example hydrophilic gels. Among the poorly soluble products, the document mentions Ciclosporin but gives no example of application of the system to cyclosporins. The document does not give any

  indication on the use of solubilizers / surfactants

  mentioned assets in association with simple mono-,

  di- or tri-glycerides of fatty acids.

  The Applicant has now found, surprisingly, that pharmaceutical compositions comprising cyclosporins as active substances, in particular Ciclosporin, make it possible to completely or partially eliminate the dosage problems encountered in the art, for example as indicated above, by using vehicle systems

  comprising tri-glycerides and mono- / di-glycerol

  fatty acid wrinkles in combination with a hydrophilic surfactant. In particular, it has been found that by using such vehicle systems it is possible to obtain oil-based compositions which are not aqueous emulsions and which do not require

  presence of solvents, co-solvents or solubilizers

  additional nutrients, for example ethanol or Labrafils and others, which have a high stability and an improved bioavailability compared to known systems of cyclosporin / fatty acid triglyceride / solvent / co-solvent, for example Sandimmun R in the form of oral saline solution. According to one

  aspect, the invention relates to pharmaceutical compositions

  oil-based products, in particular composi-

  oil-based pharmaceutical products other than

  aqueous emulsions which are free or essential

are free of ethanol.

  In particular, it has been found that

  The present invention provides an effective dosage of cyclosporine with a concomitant increase in resorption rates and bioavailability rates, and / or a reduction in the rate of resorption and / or bioavailability in each patient between patients receiving cyclosporine. It has been found, in particular surprisingly, that the compositions of the invention allow the resorption of cyclosporins in a manner which is independent or which represents a substantially reduced dependence of the relative amount of the natural surfactants, for example the acids or bile salts, present in the gastrointestinal tract of the treated patient. According to the invention, forms of administration of cyclosporine producing only a small variation in the levels of cyclosporine in the blood and / or in the serum are obtained.

  depending on the doses administered and between individuals

  due. The invention therefore makes it possible to reduce the dosage of cyclosporine necessary for an effective treatment. In addition, it allows for more accurate normalization and optimization of the permanent daily doses required by cyclosporine-treated patients as well as those required for the categories of patients undergoing treatment.

equivalent treatment.

  By a more accurate normalization of the frequency of the doses administered to each patient and the response obtained in the patient with regard to the levels in the blood and / or in the serum

  as well as the frequency of doses administra-

  and response for patient groups, it is possible to reduce controls and therefore also

  to greatly reduce the costs of treatment.

  By reducing the dosage required in

  cyclosporine and / or the normalization of

  As a result of the bioavailability obtained, the invention also makes it possible to reduce the occurrence of undesirable side effects, in particular nephrotoxic effects, in patients undergoing treatment with cyclosporine. In addition, the compositions of the invention have improved storage stability in comparison

  compositions based on ethanol or equivalent alkanols

  and are particularly suitable for example in the form of capsules, for example capsules or soft capsules. The

  compositions of the invention which are free or substantially

  Mostly free from ethanol have the particular advantage of eliminating or substantially reducing packaging problems, for example as indicated above, for example for the packaging of soft capsules. In a first aspect, the invention therefore relates to A. A pharmaceutical composition comprising: a) a cyclosporin as active substance in a vehicle comprising b) a triglyceride of fatty acids, c) a partial ester of fatty acids with glycerol or a partial or total ester of fatty acids with sorbitol or propylene glycol (for example 1,2-propylene glycol), and d) a surfactant whose balance of hydrophilic-lipophilic balance (HLB) is at least 10; with the proviso that when components (b) and (c) consist or consist essentially of

  individual components of a transesterifica-

  tion of a vegetable oil with glycerol, said composition i) is free or substantially free of ethanol or

  ii) includes Ciclosporin or [Nva] 2-Ciclos-

  porin as component (a) or iii) comprises components (a) and (d) in a

weight ratio of 1: at least 1.

  Conditions (i to (iii) above must

  be understood as not mutually exclusive.

  The invention therefore comprises compositions which satisfy

  do one or more of the above conditions.

  By the expression "pharmaceutical composition

  that "means compositions whose components

  individuals are themselves pharmaceutically acceptable

  tables, for example when considering an administrative

  oral route, that they are acceptable for oral use and when

  topical administration, that they are acceptable

  tables for topical use.

  In the compositions of the invention, the component (a) is advantageously present in a

  amount between about 2 and 20%, more

  from about 5 to 15% by weight based on the total weight of components (a) to (d). Component (a) may be one of the therapeutically useful cyclosporins, for example as indicated above. The

  component (a) preferred in the compositions of the invention

  is Ciclosporin. Another component (a) preferred

  re is [Nva] 2-Ciclosporin or cyclosporin G. Examples of suitable components (d)

  for use in the compositions of the invention

  Examples are: dl reaction products of castor oil

  natural or hydrogenated with ethylene oxide.

  Such products can be obtained according to known methods, for example by reaction of a natural or hydrogenated castor oil with ethylene oxide, for example in a molar ratio of between about 1:35 and about

  1:60, with possible elimination of polyethylene

  free glycol of the product, for example according to the methods described in German Patent Applications 1,182,388 and 1,518,819. The various surfactants sold under the trademark Cremophor are especially suitable. Particularly suitable products are: Cremophor RH 40 having a saponification number of about 50-60, an acid number <1, an iodine value <1, a water content (Fischer) <2%, a nD60 of about 1.453-1.457 and an HLB value of about 14-16; Cremophor RH 60 having a saponification number of about 40-50, an acid number <1, an iodine number <1, a water content (Fischer) of about 4.5-5%, a nD25 of about 1.453-1.457 and an HLB value of about

  -17; and Cremophor EL having a molecular weight

  (by vapor phase osmometry) of about 1630, a saponification number of about 65-70, an acid number of about 2, an iodine number of about 28-32 and a nD25

  about 1.471. The various surfactants marketed under the trademark Nikkol, for example

  Nikkol HCO-640 and HCO-60, are also suitable for

  requested. The Nikkol HCO-60 is the product of

  action of a castor oil hydrogenated with ethylene oxide having the following characteristics: acid number: about 0.3; saponification number: about 47.4: hydroxy value: about 42.5; pH (5%): about 4.6; Color APHA: about 40; melting point: about 36.0 C; freezing point: about 32.40C; H 2 O (Fischer) content: about 0.03;

  d2 fatty acid esters of a polyoxyethylene

  sorbitan, for example the mono- and tri-esters of lauric acid, palmitic acid, stearic acid and

  oleic, for example those known and

  under the trademark Tween (see Fiedler, "Lexikon der Hilfstoffe", 2nd revised and expanded edition (1981), 2, pages 972-975) including Tween products.

  [polyoxyithylene monolaurate (20) -

sorbitan]

  [Polyoxyethylene monopalmitate (20) -

sorbitan]

  [Polyoxythylene monostearate (20) -

  sorbitan], [polyoxyethylene (20) sorbitan tristearate], [polyoxyethylene (20) sorbitan trioleate], 21 [polyoxyethylene (4) sorbitan monolaurate],

  [polyoxyethylene (5) sorbitan monooleate].

  Especially preferred products of this class for use in the compositions of the invention are Tween 40 and Tween 80 above; d3 fatty acid esters of a polyoxyethylene, for example esters of stearic acid with

  polyoxyethylene, of the known and commercial type

  under the trademark Myrj (see Fiedler, cit., 1, page 228); a specially preferred product of

  this class for use in compo-

  Embodiments of the invention is Myrj 52 having a D25 of about 1.1; a melting point of about -44 ° C., an HLB value of about 16.9, an index of

* acid of about 0-1 and a saponification index

  cation of about 25-35; d4 Polyoxyethylene / Polyoxypropylene Copolymers

  and polyoxyethylene / po block copolymers

  lyoxypropylene, for example of the type known and sold under the trade names Pluronic, Emkalyx and Poloxamer (see Fiedler, cit., -2, pp. 720-723).

  this class for use in compo-

  The compositions of the invention are Pluronic F68, having a melting point of about 52 C and a molecular weight of about 6800-8975. Another preferred product of this class for use in the compositions of the invention is Poloxamer 188;

  d5 Dioctylsuccinate or di- [2-ethylhexyl] -

  succinate (see Fiedler, cit., 1, page 307); Phospholipids, especially lecithins (see Fiedler, cit., 2, pages 559-560). Lecithins suitable for use in the compositions of the invention include in particular soy lecithins; d7 Mono- and diesters of fatty acids with] 8

  propylene glycol such as propylene dicaprylate

  glycol (also known and marketed under

  Miglyol brand 840), propylene dilaurate

  ethylene glycol, propylene glycol hydroxystearate, propylene glycol isostearate, laurate

  propylene glycol, propylene glycol ricinoleate

  col, propylene glycol stearate etc ... (see

  Fiedler, loc. cit., 2, pages 760 and following).

d8 Sodium lauryl sulphate.

  The weight ratio of components (a) to (d)

  in the compositions of the invention is advantageous

  from 1: 1 to 25, more preferably from 1: 1.25 to 20, especially from 1: 1, 5 to 8 or 10, for example from 1: 2 to 5. The weight ratio of components (a) to d) is more preferably 1: at least 2. The component (a) is therefore advantageously present in the compositions of the invention in an amount of for example between 20 and 50%, more preferably between 25 and 40% by weight per relative to the total weight of components (a) and (d). It will be noted that according to the definition (A), the components (b) and (c) of the compositions of the invention

  can understand or be constituted or essential-

  individual components (b) and (c) of a single ingredient, eg a single

  or a single product. Examples of such

  including components (b) and (c) and

  Suitable for use according to the invention are mixtures of tri-glycerides of fatty acids and mono- and di-glycerides of fatty acids. Suitable products of this type include in particular the transesterification products of vegetable oils [saturated, including hydrogenated, or unsaturated], for example almond oil, peanut oil, coconut oil and palm or, preferably, corn oil, with glycerol, propylene glycol (for example

  1,2-propylene glycol) or sorbitol.

  Such transesterification products are generally obtained by heating the vegetable oil, by

  corn oil, with glycerol, propylene

  ethylene glycol or sorbitol, at an elevated temperature under an inert atmosphere and with continuous stirring, for example in a stainless steel reactor, to effect transesterification, for example glycerolysis,

glycolysis or sorbitolysis.

  The appropriate transesterification products

  required for use according to the invention

  therefore include mixtures of mono-, di- and tri-

  glycerides (i.e. glycerol mono-, di- and tri-esters) with generally low levels of

free glycerol.

  When ingredients including

  components (b) and (c) for use according to the

  are obtained by transesterification of a vegetable oil with propylene glycol or sorbitol, they also contain small amounts of propylene glycol or free sorbitol. They also contain substantial quantities of esters of these products, for example in the case of

  transesterification with propylene glycol, mono-

  and di-esters of propylene glycol and, in the case of transesterification products with sorbitol,

  mono-, di-, tri- and tetra-esters of sorbitol.

  The amount of triglyceride present in

  ingredients comprising components (b) and (c)

  use of the invention is preferably

  substantially greater than 5%, preferably from 7.5 to 12% or more by weight,

  in relation to the total weight of [(b) + (c) j in the said

  dient. The amount of free glycerol plus any free propylene glycol or sorbitol present in the ingredients comprising the two components (b) and (c) intended for use according to the invention is

  preferably less than 10%, more preferably less than

  less than 5%, especially between 1 and 2% or

  less by weight relative to the total weight of the said

  dient. The amount of monoglyceride present in the ingredients comprising the two components (b) or (c) for use according to the invention is preferably between about 25 and 50%, more preferably between about 30 and 45% by weight. weight per

  in relation to the total weight of the said ingredient.

  When a transesterification product of a vegetable oil, for example corn oil, and glycerol is used as the ingredient providing [(b) + (c)], the amount of free glycerol present in said product is preferably less than 10%, more preferably less than 5%, especially less than about 4% by weight. The amount of mono-glyceride present is preferably about 30 or 35 to 50%,

  more preferably about 35 or 40 to 45% by weight.

  The amount of di-glyceride present is preferably less than about 60%, preferably less than% by weight. The amount of triglyceride present is preferably about 10%, for example about 7.5 to 14% by weight (all percentages being based on the total weight of said product). The weight ratio of the components (b) :( c) in the transesterification products defined is therefore advantageously

from about 1: 8 to about 1: 9.

  When a transesterification product of a vegetable oil, for example corn oil, and sorbitol is used as a supplying ingredient

  [(b) + (c)], the amount of free glycerol plus

  free bitol present in said product is preferably

  less than 5%, more preferably from about 1 to 2% by weight. The amount of mono-glyceride present is preferably between about 30 and 40%, more preferably about 35% by weight (all percentages are based on total weight

of said product).

  The products of transestirification parti-

  Suitable for use according to the invention are the transesterification products of corn oil and glycirol, for example of the type marketed under the brand name Maisine. Such products contain mainly mono-, di- and tri-glycerides of linoleic acid and oleic acid as well as small amounts of mono-, di- and tri-glycerides of palmitic acid and stearic acid (corn oil itself comprising about 56% by weight linoleic acid, 30% oliic acid, about 10% palmitic acid and about 3% stearic acid). The physical characteristics of Maisine [available from Etablissements Gattefosse, 36 chemin de Genas, PO Box 603, 69804 Saint-Priest, Cedex (France)] are as follows: Approximate composition Free glycerol - 10% max. (typically 3.9-4.9% or, in more recent lots, approximately

0.2%),

  Monoglycerides - about 40% (typically 41-44.1% or, in newer batches, about 38%), Diglycirides - about 40% (or, in newer batches, about 46%), Triglycerides - about 10% (or, in more recent batches, about 12%), Free oleic acid content - about 1% Other physical characteristics of the

  Maisine are the following: acid number - max.

  about 2, iodine number - about 85-105, saponification number about 150-175, acid content

mineral = 0.

  The fatty acid content of Maisina is generally as follows: palmitic acid - approximately

  11%; stearic acid - about 2.5%; oleic acid -

  about 29%; linoleic acid - about 56%; others -

about 1.5%.

  As other transesterification products suitable for use according to the invention, mention may be made of the transesterification products of corn oil with sorbitol, for example those of the type marketed under the trade name Sorbito Glycerides from Etablissements Gattefossé, for example the Sorbito Glycerides WL 713, the composition of which is as follows: Product: Transesterification product of approximately 2

  moles of corn oil and about 1 mole of sorbitol.

  Approximate composition: free glycerol - about 1 to 2% free sorbitol) monoglycerides - about 35%

  plus: di- and tri-glycerides and mono-, di-, tri-

and sorbitol tetraesters.

  Color (Ladder Garner) - <8. Highly soluble in ethanol and chloroform / ligatively soluble in

  ethyl ether / insoluble in H 2 O. Acid Incide -

  <1; saponification number - about 160-185; index

iodine - about 110-140.

  In the case of the compositions of the invention, the components (b) and (c) of which consist essentially or consist of individual components (b) and (c) of a single ingredient, for example whose components (b) and (c) c) are constituted or consist essentially of transesterification products as described above, the weight ratio of (a) to [(b) + (c)] is advantageously 1: 0.75 to 35, preferably 1: 1 to 25, more preferably 1: 3 to especially 1: 6. When using only ingredients comprising components (b) and (c), [(b) + (c)] is preferably present in the compositions of the invention in an amount of

  from about 15 to 70% by weight, more preferably

  between 20 and 50%, relative to the weight of

  total of components (a) through (d) inclusive.

  According to a specific aspect, the invention therefore also relates to: B. A pharmaceutical composition comprising: a) a cyclosorine as active substance in a vehicle comprising: b) + c) a transesterification product of a vegetable oil and glycerol, propylene glycol or sorbitol, and d) a surfactant having an HLB value of at least 10; with the proviso that when said composition does not comprise other components (b) or (c) as defined under (A) above, said composition i) is free or substantially free of ethanol or

  ii) includes Ciclosporin or [Nva] 2-Ciclos-

  porin as component (a) or iii) comprises components (a) and (d) in a

weight ratio of 1: at least 1.

  To allow the combination of components (b) and (c) in the compositions of the invention in a preferred proportion as hereinafter described, component (b) of the compositions of the invention comprises

  preferably at least one definable ingredient such as

  a triglyceride of fatty acids, for example in the form of a material or a product which is or which consists or consists essentially of a component (b) as described above (i.e. acid triglycerides for example, which comprises at least 75%, preferably at least 90%, more preferably at least

  minus 95% by weight of components (b). In the

  of the invention, component (c) also preferably comprises at least one definable ingredient such as a partial fatty acid ester with glycerol or a partial or total fatty acid ester with propylene glycol or sorbitol, for example which is or consists essentially of a component (c) as described above, for example which comprises at least 75%, preferably at least 90%, more preferably at least 95% by weight of

components (c).

  In the compositions of the invention, components (b) and (c) more preferably comprise separate ingredients that can be combined in

  proportions (b) :( c) determined as described below.

  With regard to components (b) and (c), the compositions of the invention thus more preferably comprise a dual combination of ingredients corresponding to definition (b) and ingredients corresponding to definition (c), by example a combination of a first ingredient or ingredients made up or consisting essentially of components

  (b) and a second ingredient or ingredients

  killed or essentially consisting of components (c).

  Suitable components (b) include tri glycerides of saturated (including hydrogenated) and unsaturated fatty acids, in particular

  animal or vegetable oils. As appropriate fatty acids

  For component (b), for example, mono-, di- or poly-unsaturated

  example of 6 to 22 carbon atoms. As triglycerides

  fatty acid lines particularly suitable for use according to the invention include those having a high content of unsaturated fatty acids,

  especially mono-, di- and poly-fatty acids

  unsaturated compounds having at least 16 carbon atoms, preferably 18 or more carbon atoms, in particular

  those with a high content of oleic acid, linole-

  lique or linolenic. The triglycerides of fatty acids of particular interest are those having a linoleic acid and / or linolenic acid content of at least%, preferably at least 60% and up to 65 to 80%,

  for example when using over-refined oils.

  A first group of triglycerides of fatty acids suitable for use according to the invention

  includes triglycerides of vegetable oils including

  saturated C6-Cl2 fatty acids, for example, triglycerides of caprylic-capric acid. Examples of suitable ingredients as components (b) include fractionated vegetable oils, for example fractionated coconut oils such as those known and marketed under the tradename Miglyol (see Fiedler, loc.cit., 2, p. 615 and 616), including Miglyol 810, a caprylic-capric acid triglyceride from a fractionated coconut oil and having a molecular weight of about 520 and a C6 max fatty acid constitution. about 2%, C8 about 65-75%, C10 about 25-35%, Cl2 max. about 2%. Miglyol 810 has the following other physical characteristics: D 20 - 1.4490-1.4510; acid number - max. 10; saponification index - about

  340-360; iodine number - max. 1. Special preference

  Miglyol 812, which is a triglyceride of caprylic acid derived from fractionated coconut oil and having a molecular weight of about 520 and a fatty acid constitution - C6 max. about 3%, about 50-65%, about 35-40%, Cl2 max. about %. Miglyol 812 has the following other physical characteristics: aD20 - 1,4480-1,4500; index of

  saponification - about 330-345; iodine number - max.

  1. Other similar type ingredients suitable for use as components (b) include those known and marketed under the

  Estasan brand, for example Estasan GT 8-60 and GT 8-65.

  Estasan GT 8-60 is a fatty acid triglyceride of a vegetable oil in which the fatty acids are essentially saturated CsC10 fatty acids, in particular caprylic acid and capric acid (constitution of fatty acids - caproic acid (C6) max about 3%, caprylic acid (C8) about -65%, capric acid (COO) about 35-45%, lauric acid (C12) about 3%. Estasan GT 8-60 has the following other physical characteristics: subscript

  saponification - about 325-345; iodine number -

  max. about 1; acid number - max. about 0.1; D 20 - about 1.4481.451. Estasan GT 8-65 is also a fatty acid triglyceride of a vegetable oil, essentially comprising Cs-C fatty acids. 0 saturated, in particular caprylic acid and capric acid (constitution of fatty acids - caproic acid about 1%, caprylic acid at least about 65%, capric acid about 25-35%, acid

lauric max. about 1%).

  Other ingredients of this type are those known and marketed under the trademark Myritol, for example Myritol 318 [see Fiedler, loc. cit., 2, pp. 635-636]. Myritol 318 is a triglyceride of caprylic acid and capric acid having a saponification number of about 340,350; a clue

  of iodine - about 0.5 and nD20 - about 1.448-1.450.

  Other suitable ingredients for use as components (b) include, for example, vegetable oils such as corn oils, almond oils, kernel oils (eg apricot kernel oils), avocado oils, babassu oils, higher fatty acid coconut oils, grape seed oils, menhaden oils, olive oils, peanut oils, safflower oils, sesame oils, soybean oils and wheat germ oils, as well as animal oils such as fish oils, for example fish liver oils, for example shark oils and mink oils. The refined oils of any of the types indicated above have a

  particular interest for use according to the invention.

  In particular, refined vegetable oils with the following oleic / linoleic / linolenic acid content: oleic acid Acid acid linoleic linoleic EXAMPLE ca. 27% approx. 64% - grape seed oil approx. 4% approx. 13% approx. 76% safflower oil approx. 5% approx. 40% approx. 47% sesame oil approx. 25% approx. 54% approx. 6% soybean oil approx. 14% approx. 58% approx. 8% wheat germ oil Component (c) advantageously comprises a

  partial ester of fatty acids with glycerol, that is,

  that is, a mono- or di-glyceride of fatty acids, or an acetylated derivative thereof. Suitable ingredients for use as component (c) are preferably

  free or substantially free of all triglycerides

  fatty acid wrinkle and contain for example less than%, preferably less than 10%, more preferably

  less than 5%, for example less than 1 or 2% triglyceride

fatty acid wrinkles.

  Components (c) suitable for use in the compositions of the invention include symmetrical mono- and di-glycerides

  (ie 0-monoglycerides and a, = "- di-

  glycerides) as well as asymmetric mono- and diglycerides

  tricles (i.e., α-monoglycerides and α, -diglycerides) and their acetylated derivatives. They

  also include uniform glycerides (ie

  to say those that derive essentially from a single

  fatty acid) and mixed glycerides (ie

  say those derived from various fatty acids) and their

acetylated derivatives.

  The fatty acid residue of components (c) may comprise both fatty acid residues

  saturated and unsaturated having from 6 to 22 carbon atoms.

  The remainder of the fatty acid preferably comprises saturated or unsaturated fatty acid residues having from 8 to 18 carbon atoms, in particular 8, 10 or 14 to 18, by

  example 16 or 18 carbon atoms. Mono- and di-

  especially suitable glycerides are those in

  which the remainder of the fatty acid comprises essentially

  one or more acid residues chosen from caprylic, capric, linolenic and palmitic acids,

stearic and oleic.

  Particularly preferred components (c) are mono- and di-glycerides, in which the content of mono- / di-glycerides is from

  less than 50%, preferably at least 60%, more preferably

  at least 75% by weight, and their acetylated derivatives. Suitable components (c) include, for example, the following compounds:

  cl Mono- and di-glycerides of commercial fatty acids

  under the Imwitor brand (see Fiedler,

  loc. cit., 1, page 491), in particular the mono-

  and di-glycerides of caprylic acid and capric acid such as Imwitor 742, comprising at least 45% of mono-glycerides as described

  above and having the additional characteristics

  following factors: acid number - max.

  about 2%; iodine number max. about 1.0; saponification number about 250-280; free glycerol content - max. about 2%; and monoglycerides of stearic acid such as

  Imwitor 191, comprising at least 90% mono-

  glycerides as described above and having the following additional characteristics: melting point - about 63-66 ° C; acid number

  - max. about 3; saponification number - -

  about 160-170; iodine number - max. about 3; free glycerol content - max. about 2%, and

  the Imwitor 960K comprising between 30 and 40% mono-

  glycerides as described above and having the following additional characteristics: melting point - from about 56 to about 60 ° C, saponification number - about 155-170;

  acid number - max. about 3; iodine number -

  max. about 3; free glycerol content - max.

about 4%.

  c2 Fatty acid mono- and di-glycerides, such as those sold under the trademark Cutina (see Fiedler, cit., 1, pages 263 and 264): in particular the mono- and di-glycerides of the acid palmitic and stearic acid such as

  Cutina MD-A, comprising mono- and di-glycerol

  wrinkles as described above and having the

  following characteristics: acid number - max.

  about 8; saponification number - about -170; and glycosides of stearic acid such as Cutina GMS comprising monoglycerides as described above and having the following characteristics:

  melting - about 54-601C; acid number - max.

  about 2; saponification index - about

  162-173; iodine number - max. about 2.

  Mono-glycerides of fatty acids, such as those marketed under the tradename Myverol (see Fiedler, cit., 2, page 637), in particular mono-glycerides of C 18 fatty acids, for example linolenic acid, such as

  Nyverol 18-92, comprising at least 90% mono-

  glycerides as described above and having

  the following characteristics: acid number -

  max. about 3.0; diglyceride content - max.

  about 5%; free glycerol content - max.

about 1.2%.

  c4 Fatty acid monoglycerides marketed under the Myvaplex brand (see Fiedler, cit., 2, page 637), in particular monoglycerides of stearic acid such as those of the Nyvaplex 600 series, for example Myvaplex 600P which comprises about 94-90% of mono-glycerides such

  described above and having the characteristics

  additional issues: melting point -

about 73 C, density - about

0.92 g / cm3 at 80 ° C.

  The monoglycerides of fatty acids marketed under the trademark Estagel, for example Estagel G-18 essentially comprising monoglycerides of C16-C14 fatty acids, in particular the mono-glycerides of palmitic acid and of

  stearic acid. The minimum content of a-mono

  glycerides of Estagel G-18 is about 40%.

  The other features are:

  acid number - max. about 2; sapo index

  nification - about 162-173; iodine number -

  max. about 3; free glycerol content - max.

about 6%.

  The mono- and di-glycerides of actylated fatty acids, such as those sold under the trade name Myvacet (see Fiedler, cit., 2, pages 636-637), in particular mono-glycerides of monounsaturated fatty acids. and diacetylated e.g. monoglycerides of mono- and di-acetylated stearic acid such as Myvacet 9-40 having the following characteristics: oD50 - about 1.4468-1.4476; melting point - about 5 C; acid number - max. about 1.5; saponification number - about 375-385; and Myvacet 9-45

  having the following characteristics: "DsO -

  about 1.4465-1.4475; melting point - about 8-12.4 C; acid number - about 1.5; index of

saponification - about 375-385.

  As other particularly suitable components (c), mention may be made of mixtures of partial esters of fatty acids with glycerol with esters

  partial and total fatty acids with propylene-

  glycol, for example products containing mono-

  and di-glycerides of fatty acids and mono- and di-

  fatty acid esters with propylene glycol. Examples of such components (c) include the following: c7 Mixtures of mono- and di-glycerides of fatty acids with mono- and diesters of fatty acids

  with propylene glycol such as those

  under the Atmos brand [see Fiedler, loc.

  cit., 1, page 1561, in particular Atmos 300 in which the fatty acid residues essentially comprise residues of oleic acid and Atmos 150 in which the fatty acid residues essentially comprise residues of stearic acid. cs Mixtures of mono- and di-glycerides of fatty acids with mono- and diesters of fatty acids

  with propylene glycol such as those

  under the brand name Arlacel [see Fiedler, loc. cit., 1, pages 143144], in particular Arlacel 186 in which the fatty acid residues

  essentially comprise oleic acid.

  The weight ratio of component (b) to component (c) in the compositions of the invention is

  preferably from about 1: 0.02 to 3.0, more preferably

  from about 1: 0.1 to 2.5, especially from 1: 0.25 to

  1.25. When components (b) and (c) of composi-

  of the invention comprise the following ingredients:

  prepared, for example as described above, said ingredients are advantageously used in the same relative reports. The amount of component (b)

  in the compositions of the invention is therefore

  preferably from 10 to 50%, preferably from 20 to 40% by weight, relative to the total weight of components (a) to (d) inclusive, and the amount of component (c) is advantageously from 1 to 30%, preferably from 10 to 25% by weight relative to the total weight of the components (a)

to (d) included.

  The weight ratio of component (a) to

  components (b) + (c) in the compositions of the invention.

  Preferably, the weight ratio (a) :( b) + (c) is from about 1: 1 to 35, more preferably from about 1: 1.5 to about 30, especially

from about 1: 2 to 6.

  In accordance with the foregoing, the invention therefore also relates to C) A pharmaceutical composition as defined in A above comprising at least one ingredient consisting essentially or consisting of one or more components as defined under (b) above, D) A pharmaceutical composition as defined in A above, comprising at least one ingredient consisting essentially or consisting of one or more components as defined under (c) above; E) A pharmaceutical composition as defined in A above, in which the components (a)

  and (b) comprise separate ingredients.

  If necessary, the compositions of the invention

  Other components may include other components, for example thickeners, granulating agents, dispersing agents, flavoring agents and / or dyes or antimicrobial agents, etc.

  may also include polyethylene thickeners

  to enable the transformation into a solid or semi-solid mass intended for the preparation of

tablets or granules.

  The compositions of the invention advantageously comprise antioxidants to improve the life, for example butyl-hydroxytoluene (or BHT), butyl-hydroxy-anisole (or BHA), ascorbyl palmitate, ascorbic acid. , citric acid

or α-tocopherol acetate.

  In particular, the compositions of the invention

  advantageously include one or more stabilizers

  lisants or buffers, for example to prevent the degradation of the component (a) during implementation or storage. Such stabilizers may include acidic stabilizers such as citric acid,

  acetic acid, tartaric acid or fumaric acid

  as well as basic stabilizers, such as potassium hydrogen phosphate, glycine,

  lysine, arginine or tri (hydroxymethyl) amino-

  methane. Such stabilizers or buffering agents are advantageously added in an amount sufficient to

  obtain or maintain the pH between 5 and 7, more preferably

between 6 and 7.

  When components (b) and (c) of

  of the invention consist of a single ingredient

  which is the product of transesterification of a vegetable oil with glycerol, the compositions of the invention preferably correspond to the condition (i) as indicated under (A) above, that is to say they

* are free or substantially free of ethanol.

  More preferably, they are free or substantially

  partially free from any other component serving as

  diluent or solvent medium to component (a).

  While condition (i) is applied above in a specific case, compositions of the invention which are free or substantially free of ethanol are generally preferred. Compositions of the invention which are free or substantially free of any other diluent component or solvent medium of component (a) are also generally preferred. According to other aspects, the invention therefore also relates to: F) A pharmaceutical composition as defined under any one of (A) to (E) above, which is free or substantially free of ethanol, and ) A pharmaceutical composition as defined under any one of (A) to (E) above, which is free or substantially free from any other component serving as a diluent or

solvent medium to component (a).

  The compositions as mentioned above preferably comprise less than 2%, more preferably between 0 and 0.5 or 1% by weight of ethanol,

  relative to the total weight of the components. Compositions

  as mentioned above preferably comprise less than 20%, more preferably less than%, for example from 0 to 2.5 or 5.0% by weight of other components serving as diluent or solvent medium at

  component (a). The specific compositions of the invention

  are pharmaceutical compositions as defined under any one of (A) to (G) above, consisting or consisting essentially of components (b), (c) and (d) as a carrier for the

  component (a), i.e. without the thickening agents

  granulation agents, dispersing agents,

  flavoring agents, colors, stabilizers

  or other excipients which may also be

as additives to the vehicle.

  By diluent components is meant in particular the components used to reduce

  viscosity and / or to increase the fluidity of

  of the invention. By components serving as a solvent medium for component (a), is meant in particular

  co-solvents or other materials that increase the solu-

  bility of the components (a) in the compositions of the invention. Examples of such components include, in particular, solvents or diluents having an HLB value of less than 10, for example

  transesterification of triglycerides from a vegetable oil

  with polyalkylene polyols, such as those known and marketed under the trademark Labrafil

  (see Fiedler, supra, 2, page 539) and ethanol.

  The compositions of the invention may be applied in any suitable form, for example

  example in the form of creams, gels or others,

  for topical or ocular administration, or in the form of granules, tablets, capsules or the like, for administration by

  oral form, or in a form suitable for use in

  in the lesion, for example for the treatment of psorialis. However, the compositions of the invention are preferably administered orally. according to

  a preferred aspect, the invention therefore relates to a composition

  as defined above, in a form suitable for oral administration, particularly in unit dosage form. Particularly suitable forms for unit doses are encapsulated forms, for example

capsules or soft capsules.

  According to the invention, each unit dose

  preferably comprises from 5 to 200 mg, more preferably

  from 20 to 100 mg, for example about 25, 50 or

  mg of component (a), for example for an administration

2 to 5 times a day.

  The invention also relates to a process for the preparation of pharmaceutical compositions as defined above, process according to which one mixes

  intimately components (a), (b), (c) and (d).

  According to a preferred aspect, the invention relates to a process as described above, a method in which a component (a) is intimately mixed with a first ingredient (b) consisting essentially or consisting of one or more fatty acid triglycerides and a second ingredient (c) comprising a partial ester of fatty acids with glycerol or a

  partial or total ester of fatty acids with propylene

  glycol or sorbitol, or with a first ingredient (b) comprising a fatty acid triglyceride and a

  second ingredient (c) consisting or consisting essentially of

  substantially one or more partial esters of fatty acids with glycerol and / or one or more partial or total esters of propylene glycol and / or sorbitol, and with (d) a surfactant having a

HLB of at least 10.

  According to a particularly preferred aspect, the invention relates to a process as described above, a method in which a component (a) is intimately mixed with a first ingredient (b) consisting of

  or consisting essentially of one or more

  glycerides of fatty acids, with a second ingredient (c) consisting of or consisting essentially of one or

  several partial esters of fatty acids with glycerol

  and / or one or more partial or total esters

  propylene glycol and / or sorbitol, and (d) a surfactant.

  active having an HLB value of at least 10.

  The following examples illustrate this

  invention without in any way limiting its scope.

EXAMPLE 1

  INGREDIENTS QUANTITY (mg) a) Cyclosporine (eg Ciclosporin) 50.00 b) Miglyol 812 100.00 c) Myverol 18-92 100.00 d) Cremophore RH 40 50.00 According to the usual methods, one mixes

  intimately components (a) to (d) in the proportions

  indicated and the mixture obtained is poured into

  capsules or it is transformed into soft capsules,

each containing 50 mg cyclosporine.

EXAMPLE 2

  By proceeding as described in Example 1, soft capsules or capsules each having the following composition are prepared: INGREDIENTS QUANTITY (mg) 2a a) Cyclosporine (eg Ciclosporin) 50.00 b) Miglyol 812 100.00 c ) Imwitor 742 100.00 d) Cremophore RH 40 100.00 2b a) Cyclosporine (eg Ciclosporin) 50.00 b) + c) Maize 300.00 d) Cremophore RH 40 100.00 2c a) Cyclosporine (by (eg Ciclosporin) 50.00 b) Soybean 150.00 c) Myverol 18-92 50.00 d) Emulgin R040 * 250.00 2d a) Cyclosporine (eg Ciclosporin) 50.00 b) Sesame oils 150.00 c) Iuwitor 900K 125.00 d) Emulphor EL-719 * 150.00 2e a) Cyclosporine (eg Ciclosporin) 50.00 b) Myritol 318 75.00 c) Estagel G-18 100.00 d ) Pluronic F68 175.00 2f a) Cyclosporine (eg Ciclosporin) 50.00 b) Estasan GT 8-60 130.00 c) Arlacel 186 75.00 d) Tween 80 125.00 2g a) Cyclosporin (eg Ciclosporin) 50.00 b) + c) Maize 100.00 c) Myverol 18-92 - 200.00 d) Cremophore RH40 100.00 2h a) Cyclosporine (eg Ci closporine) 50.00 b) Miglyol 812 100.00 c) Myverol 18-92 200.00 d Cremophore RH40 100.00

  (* see Fiedler, cit., 1, page 3441.

  The compositions obtained according to the examples

  1 and 2 are appropriate for an administration of

  prevention of transplant rejection or for the treatment of autoimmune diseases, for example by administering 1 to 5 capsules per day. Equivalent compositions can be prepared by replacing Ciclosporin as component (a) with any

  which cyclosporine, for example [Nva] 2-Ciclosporin

  in an equivalent amount.

  The advantageous properties of the compositions of the invention can be demonstrated in the following tests:

  BIODAVAILABILITY STUDY OF THE COMPOSITIONS OF THE INVEN-

TION TAKEN IN THE DOG

  Groups of 8 beagle dogs (males, 11-13 kg) are used. 18 hours before the administration of the composition to be tested, the animals are deprived of food but have free access to water until administration. The compositions to be tested by gavage are then administered, followed by 20 ml of a solution of

  0.9%. Three hours after the administration of the

  to try, the animals have free access to the

food and water.

  Samples of 2 ml of blood (or 5 ml for the control assay) were taken from the saphenous vein and collected in 5 ml plastic tubes containing EDTA at -15 min. (control trial), minutes and 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours after administration. We store the samples of

blood at -18 C during the test.

  Blood samples are analyzed by RIA.

  The areas under the curve are calculated according to the method

  trapezes from plasma concentration curves

  tick / time. The analysis of the variations is carried out starting from the area under the curve (AUC), the Cmax

  (maximum concentration) and Tmax (maximum time).

  The mean values of the area under the curve (in ng hr./m1-1) and the Cmax (in ng / ml-1) calculated from the standard tests, as well as the variations of response calculated among the animals subjected tested with the same composition (CV), demonstrate high bioavailability (AUC and Cmax) associated with relatively small variation in the response of subjects for both AUC and Cmax for

  compositions of the invention, for example the composi-

  Examples of Example 1 above, in comparison with the results obtained with Sandimmune oral fluid solution.

  administered at an equivalent dose.

CLINICAL TEST

  The advantageous properties of the compositions of the invention intended for oral administration can also be demonstrated in the following clinical trials: The tests are carried out on adult volunteers, for example men with a high level of training and aged 30 to 55 years old. Each

group includes 12 people.

  The criteria for inclusion / ex-

  following: Inclusion: normal ECG; blood pressure and rhythm

  normal heart; weight - 50-95 kg.

  Exclusion: Intercurrent illness that may interfere

  absorption, distribution, metabolism, excess

  the safety or the safety of the medicine; symptoms of a clinically significant disease during the 2 weeks prior to the test; abnormal laboratory or electrocardiogram results; need for concomitant medication for the duration of the study;

  administration of any drug known to be toxic

  well-defined potential city on a vital organ, at.

  previous 3 months; administering any test medication 6 weeks before the start of the test; history of drug or alcohol abuse; loss of 500 ml or more of blood in the last 3 months; adverse reaction or hypersensitivity to the drug; history of allergy requiring a

  medical treatment; Hepatitis-B / HIV-positive.

  A complete physical exam and an ECG are

  performed before and after the test. We analyze the para-

  following meters 1 month before and after the test: Hematology: Red blood cell count, hemoglobin, hematocrit, sedimentation rate, white blood cell count, platelet count,

  leukocyte formula, fasting glucose.

Serum / Plasma:

  Total protein and electrophoresis, cholesterol

  terol, triglycerides, Na +, K +, Fe ++, Ca ++, Cl-,

  tinine, urea, uric acid, SGOT, SGPT, -GT, alkaline phosphating, total bilirubin, α-amylase; pH of urine, microalbumin, glucose, erythrocytes, body

ketones, sediments.

  The clearance of creatinine is also determined

1 month before the start of the test.

  Each patient receives the compositions

  in a randomized manner. The components are administered

  one-time oral tests, namely a

  dose of 150 mg cyclosporine, for example Ciclos-

  porin, and leave an interval of 14 days between

each administration.

  The administration takes place in the morning after a 10-hour fast during the previous night where only the absorption of water is allowed. During the following 24 hours, only caffeinated beverages are allowed. During the 12 hours following the administration, patients are not allowed to smoke. They receive a standardized lunch 4 hours

after the administration.

  Blood samples (2 ml) are taken 1

  hour before the administration and 25 minutes, one half

  hour, 1 hour, 1 hour and a half, 2 hours, 2 hours and a half, 3 hours, 3 hours, 4 hours, 4 hours, 5 hours, 6 hours, 9 hours, 12 hours, 14 hours

  hours, 24 hours, 28 hours and 32 hours after the

  tration. For the determination of creatinine, blood samples of 2 ml are taken immediately before administration and 12, 24 and 48 hours later.

  administration. For the determination of cyclosporo-

  Samples were collected in two EDTA-containing polystyrene coated tubes (1 ml each) at each time point and frozen at -20 ° C after gentle stirring. The presence of cyclosporine in whole blood is analyzed according to the specific RIA method using monoclonal and / or non-specific antibodies, the limit of detection in both

case being about 10 ng / ml.

  In the tests carried out according to the above protocol, for example by comparing the composition of Example 1 in capsule form with the oral solution of ciclosporin in the form of soft capsules (Ciclosporin-50 mg, Labrafil-150 mg, ethanol - 50 mg, corn oil 213 mg,

  final weight of the contents - 463 mg / dose)

  control, substantially high levels of bioavailability were recorded for the composition of Example 1 compared to the control composition, as indicated by AUC values (0-32 hours) and

  of Cmax. In addition, the comparison of the variation

  the concentration of Ciclosporin in the blood (such

  determined by the specific RIA method used

  After a single administration of the compositions to be tested for a dose of ciclosporin of 150 mg, a significant reduction in the response variation between all the patients receiving the composition of Example 1 was demonstrated. compared to that of all patients

receiving the control composition.

  The same or equivalent results are obtained after oral administration of the other compositions of the invention, for example as

described in Example 2.

Claims (10)

  1. A pharmaceutical composition, characterized   in that it comprises a) a cyclosporin as active substance in a carrier comprising b) a triglyceride of fatty acids, c) a partial ester of fatty acids with glycerol or a partial or total ester of fatty acids with sorbitol or propylene glycol; and d) a surfactant having a hydrophilic-lipophilic balance (HLB) value of at least 10; with the proviso that when components (b) and (c) consist or consist essentially of   individual components of a transesterifica-   tion of a vegetable oil with glycerol, said composition i) is free or substantially free of ethanol or   ii) includes Ciclosporin or [Nva] 2-Ciclos-   porin as component (a) or iii) comprises components (a) and (d) in a weight ratio of 1: at least 1.   2. A composition according to claim 1, characterized in that the component (a) is present in an amount of between about 2 and about 20% by weight relative to the total weight of the components (a) to (d) included.   3. A composition according to claim 1 or 2, characterized in that component (d) comprises the reaction product of a natural or hydrogenated castor oil with ethylene oxide, the fatty acid esters of polyoxyethylene sorbitan,   fatty acid esters of a polyoxyethylene, co-poly-   mothers or co-polymers polyoxyethylene-block   polyoxypropylene, dioctylsuccinate, di [2-ethyl-   hexyl] -succinate, phospholipids, mono- or diesters of fatty acids with propylene glycol or sodium lauryl sulphate.   4. A composition according to any one   Claims 1 to 3, characterized in that the   components (a) and (d) are present in a report   weighted from about 1: 1 to 25 [(a) :( d)].   5. A composition according to any one   claims i & 4, characterized in that   comprises a component (a) and a component (d) as specified in claim 1, and [(b) + (c)] a transesterification product of a vegetable oil with the   glycerol, propylene glycol or sorbitol.   6. A composition according to any one   Claims 1 to 4, characterized in that the   components (b) and (c) consist or consist essentially of individual components (b) and (c)   of a component [(b) + (c)] as defined in the cation 5.   7. A composition according to claim 6, characterized in that components (a) and [(b) + (c)] are present in a weight ratio of about 1: 0.75. at 35 [(a): [(b) + (c)]].   8. A composition according to any one   Claims 1 to 5, characterized in that   comprises at least one ingredient consisting of or consisting essentially of one or more components (b) as specified in claim 1 or one or   several components (c) as specified in the 1.   9. A composition according to any one   Claims 1 to 6 or 8, characterized in that   component (c) comprises a partial ester of acids   with glycerol or an acetyl derivative of this compound   is. 10. A composition according to any one   Claims 1 to 5, 8 or 9, characterized in that   components (b) and (c) are caught in a   weight ratio of about 1: 0.02 to 3.0 [(b) :( c)].