NZ270549A - Pharmaceutical composition comprising a cyclosporin dissolved in a solvent system comprising propylene glycol, a monoalcohol and a surfactant - Google Patents

Description

New Zealand Paient Spedficaiion for Paient Number £70549 FORM 5 S.9 Reg.19(4) Bfce: $260.00 NEW ZEALAND Priority Date(s): Complete Specification Fted: ..A.?4.3.\3S?..

Class: (6) A 3 Publication Date: P.O. Journal No: Insert number of Provisional Specification(s) (if any) and date(s) of filing; otherwise leave blank PATENTS ACT 1953 Number: Date: j COMPLETE SPECIFICATION 270549 Insert Title of * Invention ;WATER-DISPERSIBLE PHARMACEUTICAL COMPOSITIONS CONTAINING CYCLOSPORINS ;♦ ;Insert full name, <u!l street address nd nationality of ach) applicant l/WE BERNARD CHARLES SHERMAN, of 50 Oldcolony Road, Willowdale, Ontario, M2L 2K1, Canada, a Canadian citizen ;hereby declare the invention for which l/we pray that a patent may be granted to me/us and the method by which it is to be performed, to be particularly described in and by the following statement:- ;Indicate if following page is numbered "1 a" ;8.3.95 ;The following page is numbered "1a" - 1 - ;270549 ;la ;TECHNICAL FIELD ;The invention is directed to pharmaceutical compositions which facilitate the administration of cyclosporins. ;BACKGROUND ART ;The term "cyclosporins" as used herein shall mean the class of nonpolar polypeptides, as defined in the Merck Index, Eleventh Edition. One such cyclosporin is cyclosporin A> also known as "cyclosporine" and hereinafter referred to as "cyclosporine", known to be therapeutically active as an immunosuppressant. ;The term "composition" as used herein is to be understood as meaning any composition containing a drug along with inactive ingredients that are pharmaceutically acceptable by reason of not being excessively toxic in the quantities required. ;The term "solvent system" as used herein is to be understood to mean the material in which a drug is dissolved. The solvent system may be a single solvent or a combination or mixture of ingredients included as solvents, surfactants, diluents or for other purposes. ;Cyclosporins are hydrophobic and have low solubility in aqueous media. This makes it difficult to design pharmaceutical compositions which exhibit satisfactory absorption into systemic circulation after oral administration, or absorption into the target tissue upon topical administration. ;- 2 - ;270 549 ;The cyclosporin can be dissolved in an organic solvent (e.g. ethanol or propylene glycol), but if the solvent is water-miscible, when the composition is mixed with gastrointestinal fluid or other aqueous media, the cyclosporin will precipitate. ;Various methods of overcoming this problem are known in the prior art, but all have certain limitations. ;U.S. patent 4388307 discloses compositions comprising cyclosporine in an emulsion preconcentrate that is not water-miscible, but forms an emulsion upon being mixed into gastrointestinal fluids. The commercial product sold under the tradename Sandimmune is made according to U.S. patent 4388307, and, more specifically, comprises cyclosporine dissolved in a solvent system comprising ethanol, a vegetable oil and a surfactant. Although this composition was superior to previously known compositions, it still exhibits absorption that is less than the maximum possible and is variable. Also, the use of ethanol has disadvantages, as ethanol is volatile, and capsules of Sandimmune must be individually packaged in metallic pouches to avoid loss of ethanol by evaporation. ;U.S. patent 5342625 discloses compositions that are said to be superior in certain respects to the compositions of U.S. patent 4388307. ;The compositions of U.S. patent 5342625 comprise, in addition to the cyclosporine, a hydrophilic phase, a lipophilic phase and a surfactant. ;The hydrophilic phase is either 1-2-propylene glycol (hereinafter referred to as "propylene glycol") or a pharmaceutically acceptable alkyl or ;270549 ;tetrahydrofurfiiryl di- or partial-ether of a low molecular weight mono- ;or poly-oxy-alkanediol. ;The lipophilic phase is a solvent which is non-miscible with the hydrophilic phase, and is preferably a fatty acid triglyceride. ;It is disclosed that compositions according to U.S. patent 5342625, when added to water, disperse into droplets of smaller size than prior art compositions, thus leading to improved absorption. ;However, these compositions still have certain limitations, including: ;1) The concentration of the cyclosporin that can be achieved appears limited to about 20% by weight. This is because of the need to use both a hydrophilic phase and a lipophobic phase. ;2) Some of the solvents used may give rise to concerns about toxicity of the solvents, and ;3) Hydrophilic solvents used in the preferred compositions are volatile, which again requires packaging that will prevent evaporation. ;International Publication Number W094/25068 discloses improved compositions in which the principal solvent for the cyclosporin is an alcohol which is selected from alcohols having a boiling point above 100°C and a solubility in water of under 10 g per 100 g at 20°C. Such alcohols will hereinafter be referred to as a hydrophobic alcohols. ;270549 ;It is disclosed that such a hydrophobic alcohol can be used in place of the combination of hydrophilic and hydrophobic solvents. ;Preferred hydrophobic alcohols, within the scope of the disclosure of 5 W094/25068 are saturated alkyl alcohols having 8 to 14 carbon atoms per molecule, including 1-octyl, 2-octyl, 1-decyl, 1-dodecyl and 1-tetradecyl ;--i alcohols. ;However, when a single such hydrophobic alcohol is used as a solvent, the 10 amount of hydrophobic alcohol required to give a composition stable against precipitation is about 2.5 g alcohol per g of cyclosporin. This limits the concentration of cyclosporin that can be achieved. ;The disclosure of W094/25068 shows that cyclosporin concentration can be 15 increased by including, as a co-solvent, a second alcohol, preferably selected from benzyl alcohol and phenethyl alcohol. ;Compositions using such a combination of alcohols have advantages, in that they enable use of a reduced total quantity of solvents, thereby also enabling 20 a reduced quantity of surfactant, in order to obtain compositions exhibiting excellent dispersion in aqueous media. ;However, compositions made using benzyl alcohol or phenethyl alcohol still have a disadvantage in that benzyl alcohol and phenethyl alcohol are relatively 25 toxic. They are also somewhat volatile so that compositions comprising them may also have to be protected against evaporation. ;The object of the present invention is thus to enable water-dispersible compositions that do not require the use of benzyl alc£|ipf or phepe±tol ;5E ;-<ji ;270549 ;- 5 - ;alcohol or any other volatile solvent, that do not require use of a two-phase solvent system, and that enable a relatively high concentration of the cyclosporin. ;SUMMARY OF THE INVENTION ;It has been found that use of propylene glycol as co-solvent instead of benzyl alcohol or phenethyl alcohol is equally effective in stabilizing the composition against precipitation when a hydrophobic alcohol is used as principal solvent. This is surprising as, used alone, propylene glycol is not as strong a solvent for cyclosporine as either benzyl alcohol or phenethyl alcohol. Propylene glycol has the advantage of being both less toxic and less volatile than either benzyl alcohol or phenyethyl alcohol. ;Compositions according to the present invention will thus comprise a cyclosporin dissolved in a solvent system which comprises: ;i) As principal solvent, an alcohol selected from alcohols having a boiling point above 100°C and a solubility in water of under 10 g per 100 g at 20°C. As aforesaid, such alcohols will be referred to herein as hydrophobic alcohols. ;ii) As co-solvent, propylene glycol, and iii) a surfactant. ;It will be understood that compositions within the scope of the present invention may optionally also comprise other ingredients. ;2705aq ;- 6 - ;As the hydrophobic alcohol will generally be miscible with propylene glycol, these compositions are not two-phase as described in U.S. patent 5342625, and they have the advantages of enabling elimination of the lipophilic phase (i.e. an oil), not requiring a volatile hydrophilic solvent, and enabling higher concentrations of the cyclosporin. ;DETAILED DESCRIPTION OF THE INVENTION ;One feature of the invention is the use, as principal solvent for the cyclosporin, of a monoalcohol that has a boiling point above 100°C, and that has a solubility in water of under JO g per 100 g at 20°C. As aforesaid, such alcohols will be referred to herein as hydrophobic alcohols. Such alcohols will generally have 4 or more carbon atoms per molecule. ;Alcohols that may be used within the scope of the present invention may include any pharmaceutically acceptable alcohol having a boiling point above 100°C and a solubility in water of under 10 g per 100 g at 20°C. Preferably, the alcohol will have a boiling point above 150°C, and a solubility in water of under 1 g per 100 g at 20°C. Preferably the alcohol will have 6 to 16 carbon atoms per molecule, and more preferably 8 to 14 carbon atoms per molecule. The use of alcohols having greater than 16 carbon atoms is generally impractical as they generally have melting points above 40°C. Suitable alcohols include but are not limited to 1-octyl, 2-octyl, 1-decyl, 1-dodecyl, and 1-tetradecyl alcohols. ;Generally, as the number of carbon atoms per molecule is increased, alcohols become less hydrophilic and more hydrophobic. For example, ethyl alcohol (having 2 carbon atoms) is infinitely soluble in water at 20°C, whereas 1-butyl alcohol, (having 4 carbon atoms) has a solubility of only vj). g per UtfLfe&f r ;% ;V. HO % ;v \ ;* 7 - 270549 water, 1-hexyl (having 6 carbon atoms) has a solubility of only 0.6 g per 100 g, 1-octyl alcohol (having 8 carbon atoms) has a solubility of only 0.05 g per 100 g, and 1-decyl alcohol (having 10 carbon atoms) is essentially insoluble.

In addition to being less hydrophilic and more hydrophobic, the alcohols having more carbon atoms per molecule generally have higher boiling points and are less volatile at ambient temperature, so that use of alcohols with more carbon atoms per molecule can eliminate the problem of volatility of the hydrophilic solvents encountered with many prior-art compositions.

Another feature of the present invention is that the use of propylene glycol as a co-solvent. This enables reduction of the quantity of the hydrophobic alcohol that is required to have a composition that is stable against precipitation of the cyclosporin.

Another feature of the present invention is that the solvent system in which the drug is dissolved, in addition to including at least one hydrophobic alcohol and propylene glycol, will include at least one pharmaceutical^ acceptable surfactant, which serves to make the composition dispersible in water to form 20 an emulsion.

Examples of suitable surfactants are: i) Reaction products of natural or hydrogenated vegetable oils and 25 ethylene glycol: i.e., polyoxyethylene glycolated natural or hydrogenated vegetable oils; for example polyoxyethylene glycolated natural or hydrogenated castor oils. Particularly suitable are the products designated in the United States Pharmacopoeia and National Formulary as Polyoxyl 35 Castor Oil and Polyoxyl 40 Hy ' °\ 270549 Castor Oil, which are available under the trade names Cremaphor EL and Cremaphor RH40 respectively. Also suitable for use in this category are the various tensides available under the trade name Nikkol, e.g. Nikkol HCO-6O. Nikkol HCO-6O is a reaction product of hydrogenated castor oil and ethylene oxide. ii) Polyoxyethylene-sorbitan-fatty acid esters; e.g. mono- and tri-lauryl, palmityl, stearyl and oleyl esters; e.g. products of the type known as polysorbates and commercially available under the trade name Tween. iii) Polyoxyethylene fatty ^cid esters; for example, polyoxyethylene stearic acid esters of the type known and commercially available under the trade name Myrj as well as polyoxyethylene fatty acid esters known and commercially available under the trade name Cetiol HE. iv) Polyoxy ethy lene-poly oxypropylene co-polymers, e. g. of the type known and commercially available under the trade names Pluronic and Emkalyx. v) Polyoxyethylene-polyoxypropylene block co-polymers, e.g. of the type known and commercially available under the name Poloxamer. vi) Dioctylsuccinate, dioctylsodiumsulfosuccinate, di-[2-ethylhexyl]-succinate or sodium lauryl sulfate. vii) Phospholipids, in particular lecithins. viii) Propylene glycol mono- and di-fatty acid esters such as propylene glycol dicaprylate, propylene glycol dilaurate, propylene 270549 hydroxystearate, propylene glycol isostearate, propylene glycol laurate, propylene glycol ricinoleate, propylene glycol stearate and so forth. ix) Bile salts; e.g. alkali metal salts, for example sodium taurocholate. x) Trans-esterification products of natural vegetable oil triglycerides and polyalkylene polyols;. e.g. of the type known and commercially available under the trade name Labrafil M1944CS. xi) Mono-, di- and mono/di-glycerides, especially esterification products of caprylic or capric acid with glycerol. xii) Sorbitan fatty acid esters; for example, of the type known and commercially available under the trade name Span. xiii) Pentaerythritol fatty acid esters and polyalkylene glycol ethers; for example pentaerythrite-dioleate, -distearate, -monolaurate, -polyglycol ether and -monostearate as well as pentaerythrite-fatty acid esters. xiv) Monoglycerides; e.g. glycerol monooleate, glycerol monopalmitate and glycerol monostearate; for example as known and commercially available under the trade names Myvatex, Myvaplex and Myverol, and acetylated, e.g. mono- and di-acetylated mono-glycerides; for example as known and commercially available under the trade name Myvacet. xv) Glycerol triacetate or (1, 2, 3)-triacetin; and 270549 xvi) Sterols and derivatives thereof, for example cholesterols and derivatives thereof, in particular phytosterols; e.g. products comprising sitosterol, campesterol or stigmasterol, and ethylene oxide adducts thereof, for examples soya sterols and derivatives thereof, such as known under the trade name Generol.

Suitable surfactants will not be limited to those listed above, but will be understood to include any compound which causes the composition to be more easily dispersible in water.

When the surfactant also is an effective solvent for the drug, it may be incorporated not only as surfactant, but as an additional carrier or co-solvent, to reduce the amount of hydrophobic alcohoi and/or propylene glycol required.

It will be understood that not all surfactants will act equally well with all alcohols to improve dispersion, and moreover, not all alcohols will work equally well as suitable solvents for all cyclosporins. Determination of suitable combinations of alcohols and surfactants for particular appl.nations within the scope of the invention will be within the capability of persons skilled in the art of product formulation.

Compositions in accordance with the invention may contain other ingredients in addition to the drug, one or more hydrophobic alcohols, propylene glycol, and one or more surfactants.

For example, the solvent system in which the drug is dissolved may include, in addition to the foregoing, one or more other ingredients that are included as co-solvents or diluents. 270549 A composition in accordance with the invention may also contain, for example, a thickening agent (i.e. viscosity increasing agent). Suitable thickening agents may be any of those known and employed in art, including, for example, pharmaceutically acceptable polymeric materials and inorganic thickening agents. However, where oral administration is intended, the use of thickening agents as aforesaid will generally not be required. Use of thickening agents is, on the other hand, indicated, e.g. where topical application is foreseen.

Compositions in accordance with the invention may also include one or more further ingredients; such as d.iluents, anti-oxidants, flavouring agents and so forth.

Compositions in accordance with the invention may be liquids at ambient temperatures or they may be solids prepared, for example, by use of hydrophobic alcohols or surfactants with melting points above ambient temperatures. The ingredients may be blended at temperatures above the melting point and then used to fill capsules while still molten, or cooled to form solids. The solids may be ground into granules or powder for further processing; for example, filling capsules or manufacture of tablets.

The capsules or tablets may be further processed by applying coatings thereto.

Especially where oral administration is contemplated, compositions in accordance with the invention may comprise end dosage forms for administration as emulsion preconcentrates. For example the emulsion preconcentrate may be directly used as liquid for oral ingestion, parenteral use, or topical application or it may be encapsulated into gelatin capsules for oral ingestion. 270549 However, the present invention also provides pharmaceutical compositions, in which the emulsion preconcentrate is further processed into an emulsion. Thus where oral administration is practiced, emulsions obtained, e.g. by diluting an emulsion preconcentrate with sufficient water or other aqueous medium (for example, a sweetened or flavoured preparation for drinking), may be employed as formulations for drinking. Similarly, where topical application is foreseen, compositions comprising an emulsion preconcentrate, a thickening agent, and water will provide an aqueous emulsion in gel, paste, cream or like form.

It should be noted that the droplet size of the emulsion formed when an emulsion preconcentrate according to the invention is dispersed in water will depend upon the identity and quantity of the ingredients used.

Generally, for a given composition, droplet size will decrease as the amount of surfactant is increased. Generally, smaller emulsion droplet size will enable improved absorption, so that there is usually an advantage to using more surfactant to obtain decreased droplet size. However, increased quantity of surfactant may also imply increased toxicity from the surfactant, increased cost and increased size of the dosage form of any desired strength. Moreover, if enough surfactant has been used to achieve absorption close to the maximum achievable, little is to be gained by adding more surfactant.

Hence, it will be understood that the quantity of the surfactant must be selected as sufficient to achieve maximum or near-maximum absorption without use of more than needed so as to avoid excessive toxicity, cost, and dosage form size. 270549 appropriate manner and form; e.g. orally, as liquids or granules or in unit dosage form, for example in hard or soft gelatin encapsulated form, parenterally or topically; e.g. for application to the skin; for example in the form of a cream, paste, lotion, gel, ointment, poultice, cataplasm, plaster, dermal patch, powder, topically applicable spray, or the like, or for ophthalmic application; for example in the form of an eye-drop, lotion or gel formulation. Readily flowable forms may also be employed; e.g. for intralesional injection for the treatment of psoriasis, or may be administered rectally. Compositions in accordance with the invention are, however, primarily intended for oral or topical application, including application to the skin or eyes. i The relative proportion of drug and other ingredients in the compositions of the invention will, of course, vary considerably depending on the particular type of composition concerned; e.g. whether it is an emulsion preconcentrate or emulsion, the route of administration, and so forth. The relative proportions will also vary, depending on the identity and particular function of ingredients in the composition; for example, in the case of a surfactant component of an emulsion preconcentrate, on whether this is employed as a surfactant only or both a surfactant and a co-solvent. The relative proportions will also vary depending on the particular ingredients employed and the desired physical characteristics of the product composition, e.g. in the case of a composition for topical use, whether this is to be a free flowing liquid or a paste. Determination of workable proportions in any particular instance will generally be within the capability of persons skilled in the art. All indicated proportions described herein are accordingly to be understood as being examples and not as not limiting the invention in its broadest aspect.

Compositions for topical use suitably comprise one or more carriers or diluents and/or other ingredients (e.g. thickening agents, emulsifying agents, Ii w 270549 agents, moisturizing agents, colourants and so forth) providing a suitable carrier.

Selection of excipients for the preparation of such formulations will, of course, be determined by the type of formulation desired as well as the particular condition to be treated, the area to be treated, and the effect desired. Some conditions will more suitably be treated with hydrophobic, e.g. fat-based compositions, for example compositions in accordance with the invention comprising a petrolatum based ointment or cream as carrier medium. In contrast, compositions for use in the treatment of some conditions will more appropriately be treated with more hydrophilic compositions.

By use of suitable individual carrier ingredients or mixtures thereof, compositions may be obtained in liquid or semi-solid form.

BEST MODE OF CARRYING OUT THE INVENTION Preferred hydrophobic alcohols for use as principal solvent for the drug are monoalcohols having a boiling point above 150°C, a melting point under 40°C, and a solubility in water of 1 g per 100 g at 20°C. Especially preferred alcohols are 1-octyl, 2-octyl, 1-decyl, 1-dodecyl, and 1-tetradecyl alcohols.

Preferred surfactants are reaction products of natural or hydrogenated vegetable oils and ethylene glycol; i.e., polyoxethylene glycolated natural or hydrogenated vegetable oils.

Especially preferred surfactants are polyoxyethylene glycolated natural or hydrogenated castor oils, including those designated int he United States Z'0549 Pharmacopoeia and National Formulary as Polyoxyl 35 Castor Oil and Polyoxyl 40 Hydrogenated Castor Oil.

The invention will be more fully understood by the following examples which are illustrative but not limiting of compositions in accordance with the present invention.

Example 1 4 The following ingredients were placed in a container in the proportions shown, after the 1-dodecyl alcohol was liquified by warming it to above 25 °C: 1.0 1.0 M 3.5 Upon blending, a clear solution was formed.

Example 2 The following ingredients were placed in a container in the proportions shown, after the 1-tetradecyl alcohol was liquified by warming if to above 40°C: cyclosporine 1.0 1-tetradecyl alcohol 1.0 cyclosporine 1-dodecyl alcohol polyoxyl 35 castor oil propylene glycol 270549 polyoxyl 35 castor oil propylene glycol 0.5 1.0 3.5 As with example 1, upon blending a clear solution was gradually formed. Example 3 The solution of example 2 was used in hot liquid form to fill two-piece hard gelatin capsules intended for oral administration. The amount of solution per capsule was 350 mg so that each capsule contained 100 mg of cyclosporine.

Upon cooling to room temperature after the filling process, the solution solidifies, so that there is no leakage from the capsules, even if the capsules are not sealed.

The solutions of each of examples 1 to 2 are directly useable as drops for oral ingestion or as a liquid for opthalmic or topical use.

Alternatively, they may be further processed in various ways previously described, including, for example, their incorporation into gelatin capsules (as in example 3) or tablets for oral ingestion, or into emulsions and various other forms for oral or topical use.

For example, they may be mixed into water or other aqueous media and used as a drink. Alternatively, they may be incorporated into a cream, ointment, gel or the like by combination with further additives, e.g., thickening agents, paraffins, etc. as hereinbefore described. -

Claims (2)

1. 270549 INDUSTRIAL APPLICABILITY From the foregoing description it will be apparent that in the present invention there is provided an improved pharmaceutical composition which permits the more efficient administration and absorption of cyclosporins. &:■ tr, C W .At 10 - 18 - WHAT I /WE CLAIM IS: 2.7 0 ^ ^ ^ 1. A pharmaceutical composition comprising a cyclosporin dissolved in a solvent system, said solvent system comprising propylene glycol, at least one monoalcohol having a boiling point above 100°C and a solubility in water inferior to 10 g per 100 g at 20°C, and at least one surfactant, said solvent system and said composition optionally also comprising other ingredients.
2. 2. A composition according to claim 1 wherein the monoalcohol has a boiling point above 150°.C and a solubility in water inferior to 1 g per 100 g at 20°C. 15 3. A composition according to claim 1 or 2 wherein the cyclosporin is cyclosporine. A composition according to claim 1/ 2 or 3 wherein the monoalcohol is selected from saturated alkyl alcohols having at least 6 carbon atoms 20 per molecule. 5. A composition according to claim 1, 2 or 3 wherein the monoalcohol has from 6 to 16 carbon atoms per molecule. 25 6. A composition according to claim 5 wherein the monoalcohol is 1-dodecyl alcohol. 7. A composition according to claim 5 wherein the monoalcohol is 1-tetradecyl alcohol. I u s:P iss5 10 - 19 270549 8. A composition according to claim 1 wherein said surfactant is a polyoxyethylene glycolated natural or hydrogenated vegetable oil. 9. A composition according to claim 8 wherein the surfactant is a polyoxyethylene glycolated natural or hydrogenated castor oil. 10. A composition according to claim 1 contained within a gelatin capsule suitable for oral administration. J. D.' HARDTE'& CO. Patent Attorneys for the Applicant(s). ,J,' SEP 1535