GB2098865A - Topical pharmaceutical compositions - Google Patents

Topical pharmaceutical compositions Download PDF

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GB2098865A
GB2098865A GB8209940A GB8209940A GB2098865A GB 2098865 A GB2098865 A GB 2098865A GB 8209940 A GB8209940 A GB 8209940A GB 8209940 A GB8209940 A GB 8209940A GB 2098865 A GB2098865 A GB 2098865A
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composition
skin
active agent
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Sandoz Ltd
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/10Dispersions; Emulsions
    • A61K9/107Emulsions ; Emulsion preconcentrates; Micelles
    • A61K9/1075Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers

Abstract

A skin penetration pharmaceutical composition incorporating a difficultly skin-penetrable pharmacologically active agent, wherein the composition is in the form of a microemulsion formed from skin compatible excipients.

Description

SPECIFICATION Topical pharmaceutical compositions This invention relates to topical pharmaceutical compositions, particularly those containing pharmacologically active agents which only difficultly penetrate the skin horny layer.

The therapeutic efficiency of a topical pharmaceutical composition depends upon inter alia the availability of the pharmacologically active agent for absorption and the sl < in-penetrability of the active agent. Before any topically applied pharmacologically active agent can act at its site of action whether in the deeper dermal layers below the horny layer or elsewhere in the body it must penetrate the barrier of the horny layer of the skin (stratum corneum). The penetration of the stratum corneum is the rate-limiting step of the total percutaneous process and is accompanied by the creation of a reservoir of pharmacologically active agent, i.e. the deposition of pharmacologically active agent on and in the layer.In the rare case the pharmacologically active agent is normally liquid and penetrates the skin layer efficiently, e.g. isosorbide dinitrate or glyceryl trinitrate. Otherwise various methods must be employed to obtain sufficient penetration of the pharmacologically active agent through the horny layer, especially for active agents which are generally administered in solid form. Often the pharmacologically active agent is capable of penetrating the skin horny layer when applied to the sl < in in a conventional system such as a triglyceride or paraffin ointment, but has a penetration flux of less than about 10-9 Mol cm-2 hour-', e.g. 10-'0 Mol cm-2 hour-'. Such pharmacologically active agents are hereinafter referred to as difficultly skin-penetrable pharmacologically active agents.

One method to increase the penetration rate is to dissolve the skin-penetrable pharmacologically active agent in a non-toxic solvent which is skin compatible e.g. that does not cause skin irritation over an extended period of time as indicated in standard tests using human skin or more sensitive guineapig skin. The solutions may be applied in the form of macroemulsions, i.e.

opaque oil-in-water or water-in-oil systems formed from water and water immiscible organic solvents in the presence of an emulsifier.

Such systems suffer from disadvantages especially in the case of difficultly skin-penetrable pharmacologically active agents.

We have now found that skin penetration pharmaceutical compositions wherein the composition is in the form of a microemulsion have particularly advantageous properties in respect of difficultly skin-penetrable pharmacologically active agents.

A recent review on microemulsions is by M. Rosoff p. 405 in Progress in Surface and Membrane Science 12, 1978 Academic Press. A microemulsion is generally recognised to be a coloured or colourless (oil-in-water or water-in-oil) emulsion wherein the diameter of the particles or droplets are less than about 1 500 Angstrom units (150 nm) which is less than 1/4 of the wavelength of light. They do therefore not scatter visible light, the diameter of the particles or droplets arising from e.g. any micellar aggregate structure present being sufficiently small. The emulsion thus appears transparent when viewed by optical microscopic means. It may be isotropic or an isotropic. An anisotropic structure may however be observable using x-ray techniques.The particles in a microemulsion may be spherical but other structures are feasible, e.g. liquid crystals with lamellar, hexagonal or isotropic symmetries.

Usually microemulsions are produced from an emulsifier (a surfactant) and a co-emulsifier (i.e.

a co-surfactant, polar additive, co-solubilizer) which lowers the interfacial tension between the oil-in-water phases to a very small amount (typically less than 1 dyne/cm). The microemulsions often form practically spontaneously and represent a single thermodynamically stable phase. In contrast, macroemulsions are thermodynamically unstable two phase systems, and in their formation energy suppiy in the form of heating or rapid agitation is required.

Microemulsions are weli known in other fields, e.g. cosmetic preparations, floor polishes, paints and foods. However, the formulation of microemulsions is to a certain extent largely empirical (see for example p. 34-56 in Microemulsions Theory and Practice, Ed. L. Prince, 1977) and up to now no skin penetration pharmaceutical composition for the systemic administration of a difficultly skin-penetrable pharmacologically active agent has been produced from skin compatible excipients. J. Ziegenmeyer and C. Fuhrer in Acta Pharmaceutica Technologica 1980, 26 (4) p. 273-275 have disclosed a microemulsion pharmaceutical composition containing 1% tetracycline hydrochloride and decanol. However, the composition is not capable of producing a systemic therapeutic effect as the tetracycline concentration in the pharmaceutical composition is.too low.More importantly decanol is not skin compatible. For example in sensitive animal skin irritation tests, moderate irritation of guinea pig skin and severe irritation of the rabbit skin has been found, see for example Industrial Hygiene and Toxicology Second Revised Edition, Editor F. Patty, Vol. il, (1962), p. 1467, Interscience Publishers, John Wiley, New York and London. In less sensitive tests using human skin exposed to decanol over a 24 hour period, significant irritation has been observed, see-for example p. 753 W. Kästner, J. Soc. Cosmet. Chemists (1974) 28, 741-754. Additionally the specific hydrocarbon solvents suggested are not applicable for man.

We have found that microemulsions may be made containing pharmacologically active agents and skin compatible excipients which show particularly advantageous penetration properties producing a penetration flux sufficient to produce a therapeutic effect in the deeper dermal layers or through the systemic circulation as indicated in trials mentioned hereinafter.

In one aspect the present invention provides a skin penetration pharmaceutical composition incorporating a skin-penetrable pharmacologically active agent, wherein the composition is in the form of an microemulsion formed from skin compatible excipients.

In another aspect the present invention provides a method of enhancing the penetration of a skin-penetrable pharmacologically active agent through the skin which comprises applying the active agent to the skin in the form of a microemulsion consisting of skin compatible excipients.

In a further aspect the present invention provides the use of a microemulsion consisting of skin compatible excipients to administer percutaneously a skin-penetrable pharmacologically active agent.

In yet a further aspect the present invention provides a process for the production of a skinpenetrable pharmaceutical composition which comprises forming a microemulsion from water and a skin-penetrable pharmacologically active agent and skin compatible excipients capable of functioning as a water-immiscible organic solvent, an emulsifier, and a co-emulsifier.

The microemulsions may be produced in conventional manner for the preparation of topical pharmaceutical compositions. The skin compatible pharmacologically active agent, waterimmiscible organic solvent, water, emulsifier and co-emulsifier may be mixed, conveniently at a maximum of 100"C, e.g. from about 60 to about 95"C and the mixture is cooled. It is not important that a microemulsion be formed above 32do.

If a microemulsion is formed above 32"C then the phase inversions should preferably be reversible. Indeed it is quite common that a milky macroemuision may be formed at high temperatures which on cooling passes through one or more cloudy transitional phases alternately with microemulsion phases.

Desirably a microemulsion is produced throughout the temperature range of from about 20"C to about 32"C, preferably from about 15"C to about 35"C.

The water-immiscible organic solvent may be for example a hydrocarbon or lipophilic ester.

An emulsifier is present to form an oil-in-water or water-in-oil emulsion wherein the oil is the water-immiscible organic solvent. The co-emulsifier contributes to the formation and the stability of the microemulsion.

The chemical structure or chainlength of the co-emulsifier is a governing factor in controlling the size of the droplets or particles in the emulsions and should match the structure or chainlength of the hydrocarbon part of the emulsifier. The co-emulsifier should be compatible with the water-immiscible organic solvent forming the lipophilic phase. The organic solvent emulsifier and co-emulsifier should also be compatible with the pharmacologicaily active agent.

Naturally it is possible that the same excipient acts as a water-immiscible organic solvent and simultaneously as a co-emulsifier. Conveniently different excipients are used as organic solvent and co-emulsifier, however. The microemulsions may be colourless or coloured, e.g. yellow.

A suitable combination of an emulsifier with a co-emuisifier may be, for example, a watersoluble non-ionic emulsifier and a fatty alcohol of a suitable chain length. Another suitable combination may be a mixture of water-soluble and water-insoluble non-ionic tensides. Conveniently at least two of the water-immiscible organic solvent, co-emuisifier and emulsifier has a chain length moiety of 1 2 to 20 carbon atoms.

For any particular skin compatible pharmacologically active agent, water-immiscible organic solvent, water, emulsifier, and co-emulsifier system the relative amount of excipients can be varied and full phase equilibria diagrams may be drawn. It is sometimes more convenient merely to obtain a microemulsion at any temperature, even above room temperature, from one set of excipients in order to show they are compatible and then vary the amounts slightly to produce a suitable microemulsion at room temperature. As a very rough guide the microemulsion may contain: a) 0.01 to 15% of skin compatible skin-penetrable pharmacologically active agent, b) 5 to 30%, e.g. 10 to 30%, of skin compatible water-immiscible organic solvent, c) 10 to 30% of skin compatible emulsifier, d) 4 to 30% of skin compatible co-emulsifier, and e) 15 to 55% water.

Where the same compound may act as, e.g. both water-immiscible organic solvent and coemulsifier, and in particular when another co-emulsifier or organic solvent is omitted then a part of the concentration of the compound (together with any other water-immiscible solvent present) may be reckoned as water-immiscible solvent and a part (together with any other co-emulsifier present) as co-emulsifier. Where the same excipient acts as both water-immiscible organic solvent and co-emulsifier and there is no co-emulsifier or organic solvent present then this excipient may be present from 9 to 60% of the composition.

The microemulsions of the invention may be in the form of liquids or preferably in the form of gels, which are semi-viscous, containing less water. Some microgels may have appropriate viscoelastic properties to form swinging gels.

In respect of any of the excipients mentioned hereinafter any aliphatic carboxylic acid may be straight-chain or branched and saturated or unsaturated, preferably with one or two double bonds. Any aliphatic alcohol is a univalent alcohol unless otherwise mentioned, and is preferably a secondary or especially a primary alcohol. They are branched or preferably straight-chain and are unsaturated with preferably one or two double bonds or especially saturated. Any glyceryi ether or ester is primarily etherified or esterified at one or both of the terminal glyceryl hydroxy groups.

Suitable skin compatible excipients may be the following: 1) an ester of an aliphatic (C318) alcohol with an aliphatic (C,0 22) carboxylic acid, or 2) a hydrocarbon having a straight carbon (C12 32) chain substituted by from 6 to 1 6 methyl.

groups and having up to 6 double bonds, may be suitable water-immiscible organic solvents.

Examples of class 1) include isopropyl laurate, hexyl laurate and decyl laurate, isopropyl myristate and lauryl myristate.

Particularly suitable examples are isopropyl laurate, hexyl laurate and isopropyl myristate, especially hexyl laurate.

Examples of class 2) include terpenes such as polymethylbutanes and polymethylbutenes, e.g.

2, 6, 10,1 5,1 9,23-hexamethyl-2,6, 1 0,1 4,1 8,22 tetracosahexaene, also known as squalene (C30H50) and the perhydro analogue, squalane. A particularly suitable example is squalane.

Skin compatible excipients chosen from 3) a mono-ester of ethylene glycol or propylene glycol with an aliphatic (C622) carboxylic acid, 4) an ester of an aliphatic (C1222) alcohol with lactic acid, or 5) a mono-or diester of glycerol with an aliphatic (C622) carboxylic acid, may be suitable for use as water-immiscible organic solvents and/or co-emulsifiers.

When a excipient of any of classes 3), 4) or 5) is present as an organic solvent, then the same or different excipient may be present as a co-emulsifier.

Examples of class 3) include propylene glycol mono-laurate and propylene glycol monomyristate and preferably propylene glycol monolaurate. An example of class 4) is myristyl or preferably lauryl lactate. An example of class 5) is glyceryl caprylate.

Any skin compatible excipients chosen from 6) an ester of a poly(2-7)ethylene glycol glycerol ether having at least one free hydroxyl group and an aliphatic (C622) carboxylic acid, may be suitable for use as water-immiscible solvents or co-emulsifiers.

Some of this class may be water-miscible when for example the polyethylene glycol moiety has a higher molecular weight, and so will not be suitable as organic solvents, but they may be suitable co-emulsifiers. An example is poly(7)ethylene glycol glyceryl cocoate.

If the excipient is a transesterification product of a vegetable oil triglyceride and a polyethylene glycol of molecular weight 200 to 400, e.g. as described in USP 3,288,824, the contents of which are hereby incorporated by reference, then the products may be water-immiscible and suitable for use as an water-immiscible organic solvent.

Skin compatible excipient chosen from 7) aliphatic (C1222) alcohol, or 8) an ester of having at least one hydroxyl group of a poly-(2-1 0)-glycerol with an aliphatic (C622) carboxylic acid, may be also suitable co-emulsifiers.

Examples of class 7) include dodecanol, tetradecanol, oleylalcohol, 2-hexyldecanol, and 2octyl-decanol. Particularly suitable examples include tetradecanol and especially dodecanol.

Preferably the alcohol is liquid at 32"C.

Skin compatible excipients chosen from 9) a mono-ether of a poly-ethylene-glycol with an aliphatic (C,218) alcohol, having an HLB value of from 10 to 18, or 10) an ester of an aliphatic (C622) carboxylic acid with a) a polyethylene glycol b) a saccharose c) a sorbitan or d) a poly-ethylene glycol sorbitan ether, the ester having an HLB value of from 10 to 1 8, may be suitable emulsifiers.

Preferably the emulsifiers have an HLB value of from 1 2 to 1 5 (HLB values are an indication of the hydrophilic-lipophilic balance in an emulsifier and have been discussed extensively in the literature, see for example Pharm.Act.Helv. (1969) 44, 9 and H.P.Fiedler, Lexicon der Hilfsstoffe für Pharmazie, Kosmetic und angrenzende Gebiete, 2nd Edition, 1981, Editio Cantor AG, BRD).

A preferred example of class 9) is commercially available polyoxyethylene-(10)-oleyl ether.

Preferably the microemulsions are made up from excipients from class 1) and 2) as waterimmiscible organic solvents; especially class 1); class 7) as co-emulsifier and class 9) as emulsifier.

The exact choice of organic solvent, emulsifier and co-emulsifier will depend on inter alia the pharmacologically active agent used.

The pharmacologically active agent may be any compound which can, penetrate the skin horny layer, e.g. of molecular weight up to about 3,000, although higher molecular weight compounds may possibly be used.

In general the molecular weight of the pharmacologically active agent is conveniently below 1 000. Conveniently the active agent has a good hydrophilic/lipophilic balance. The molecule of the active agent for example may be conveniently structurally compact, may contain aromatic groups and conveniently does not contain many reactive groups such as hydroxyl groups.

The microemulsions of the invention are capable of containing very high amounts of active agents, e.g. from 5% up to 15% or even up to 20% of the total weight. When a systemic action is desired, the pharmacologically active agent should be sufficiently active to be able to produce a systemic therapeutic effect when penetration the skin at rate of the order of 10-8 Mole cm-2 hour-'. When a local action in the deeper dermal layer is required, then a skin penetration flux of 10-9 Mole cm-2 hour-' may be sufficient. Suitable agents may be for example those with an, e.g. oral, daily dose of-about 0.1 to about 20 mg, preferably up to 1 mg.

The microemulsions of the invention may be indicated for the systemic administration of any active agent. They may be conveniently used for prophylactic agents and myotonolytics. The microemulsions of the invention may be indicated for the administration of pharmacologically active agents which act under the horny layer, e.g. anti-acne agents and anti-fungal agents.

Examples of active agents include (E)-N-methyl-6 , 6-dimethyl-N-(naphthylmethyl)hept-2-en-4-inyl- 1-amine, prbquazone, (E)-N-methyl-N-(l -naphthyl methyl)-3-phenyl-propen-2-yl-amine (hereinafter naftifin), 4-( 1 -methyl-4-piperidylidene)-4H-benzo[4, 5cyclohepta-[1 ,2-b]thiophen- 1 0(9 H)-one (hereinafter ketotifen), 4-(1 -methyl-4-piperidylidene)-9 , 1 O-dihydro-4H-benzo-(4,5)-cyclohepta(l ,2-b)-thiophene (hereinafter pizotifen), griseofulvin, fluocinolone acetonide, Triamcinolone acetonide, and 14-0-[5-(2 amino-1,3,4-triazol-yl)thioacetyl]-dihydro-mutiline, and preferably (+ )-1 -methyl-2-[2-(a-methyl-p-chlorndiphenyl-methoxy)-ethylpyrrnlidine (hereinafter clemastine) and especially 5-chloro-4-(2-imidazolin-2-ylamino)-2, 1 ,3-benzothiadiazole (hereinafter tizanidine).

In respect of clemastine a microemulsion preferably contains any of the following concentra tons: 5 to 15% of clemastine.

5 to 30% of an water-immiscible organic solvent.

1 5 to 25% of an emulsifier.

5 to 25% of a co-emulsifier.

10 to 45% of water.

More preferably a microemulsion contains any of the following concentrations: 7.5 to 12.5% of clemastine.

7.5 to 28.5% of water-immiscible organic solvent.

19.5 to 22% of an emulsifier.

7.5 to 22.5% of a co-emulsifier.

1 3 to 42% of water More especially a clemastine microemulsion contains any of the following concentrations: 8 to 12% of clemastine.

8 to 27% of water-immiscible organic solvent.

20 to 21% of an emulsifier.

8 to 21% of a co-emulsifier.

1 5 to 40% of water.

The excipients are preferably chosen from class (1) as defined above, as organic solvent.

The excipients of class (3) as defined above may be present as organic solvent or coemulsifier, especially propylene glycol mono-laurate. The co-emulsifier alternatively is an excipient of class (6) as defined above especially poly(7)ethylene glycol glyceryl cocoate, or propylene glycol myristate. The preferred emulsifier is chosen from class (9) as defined above, especially polyoxyethylene (10) oleyl ether e.g. having an HLB value of about 1 2 to 1 3.

With clemastine microgels containing high concentrations of clemastine can be produced whereas it is very difficult to produce stable macroemulsions containing such high clemastine concentrations.

In the respect of tizanidine a microemulsion preferably contains any of the following concentrations: 6 to 10% of tizanidine.

1 5 to 25% of water-immiscible organic solvent.

1 5 to 25% of an emulsifier.

5 to 10% of a co-emulsifier.

30 to 35% of water.

Preferably the microemulsion contains any of the following concentrations: 7.5 to 8.5% of tizanidine.

19.5 to 21.5% of water-immiscible organic solvent.

1 9 to 22% of an emulsifier.

5.5 to 21.5% of a co-emulsifier.

32 to 42% of water.

More particularly the microemulsion contains any of the following concentrations: 8 to 8.4% of tizanidine.

20 to 21 % of water-immiscible organic solvent.

20 to 21% of an emulsifier.

6.2 to 8.4% of a co-emulsifier.

33 to 42% of water.

Naturally the choice of water-immiscible organic solvent, emulsifier and co-emulsifier for a microemulsion system will vary from pharmacologically active agent to pharmacologically active agent, and in some cases a particular excipient may be suitable in one system as e.g. an waterimmiscible organic solvent and in another system as an e.g. co-emulsifier.

The pH of the pharmaceutical composition may be adjusted to a skin compatible pH with appropriate acids or bases, preferably weak acids or bases e.g. lactic or acetic acid. It is preferred that the pharmacologically active agent is at least partially present in free form, e.g.

free base form as the skin penetration may be increased. Conveniently the pH of the microemulsions are weakly acidic.

Other skin compatible agents may be present, e.g. water-miscible solvents such as propylene glycol and ethanol and isopropanol, or water soluble film-forming agents used in cosmetic preparations, e.g. partially hydrolysed collagen yielding medium-weight polypeptides, to diminish solvent evaporation after rubbing on the skin.

Naturally the microemulsion should be composed of components that are skin compatible.

The components should be non-toxic, non-allergic and well-tolerated by the skin tissue. Such components can be chosen by standard acute and chronic tests.

The tests may be effected on human skin or with more sensitive animal skin, e.g. guinea-pig skin.

The microemulsions of the invention are indicated for use in the percutaneous administration of pharmacologically active agents because of the skin penetration enhancing effects, and the capacity of the microemulsions to contain large amounts of pharmacologically active agents.

The skin-penetration enhancing effect may be observed in standard in vitro and in vivo tests for example using human skin.

One in vitro test is the well-known diffusion test which may be effected according to the principles described by H. Schaeffer et al in Adv.Pharmacol.Ther.[Proc.7th lnt.Cong.Pharmacol.] 9, 223-235 (1978) ed by Y. Cohen, Pergamon, Oxford (1979); H. Schaeffer et al pp. 80-94 in Current Problems in Dermatology 7, Ed. G.A. Simon et al., Karger, Basel (1978); and J.M.

Franz et al, Arch. Dermatol. Res (1981), 271:275-282, using isolated human skin.

Microemulsions with the pharmacologically active agent in radio-active labelled form are applied to isolated pieces of unbroken human abdominal skin of about 2 square centimetres in area, at an amount of about 5 to about 10 mg of microemulsion per square centimetres. The skin is maintained at 32"C as a barrier between an upper chamber and physiological saline placed in a lower chamber. After 100,300 and 1000 minutes at 32"C the skin is fixed on a stopper. The residue is removed from the skin surface by a cotton swab and the radioactivity measued. The horny layer is removed by stripping and the radioactivity is determined in each individual stripping. The remaining skin is congealed and sliced into sections of about 20-40 with a microtome. The radioactivity in the various slices is determined.The radioactivity in aqueous saline in contact with the underside of the skin is also measured.

Since the penetration of the pharmacologically active agent through the horny layer represents in general the rate limiting step, the amount of pharmacologically active agent that has passed the horny layer is relevant to the systemic activity. This fraction of pharmacologically active agent contained in the different dermal layers, i.e. epidermis, upper corium (ca 800 microns thick), lower corium (ca 1000 microns thick) and sub-cutis (ca 1 500 microns thick), would in vivo be removed by the capillary system into the blood stream and hence into the general circulation.

For convenience the fraction of the pharmacologically active agent that has penetrated the horny layer after 1 6 hours and is present in the deeper dermal layers is measured to give a mean percutaneous penetration flux (F) on the basis of a number of trials (n) as well as a percutaneous resorption quota in % of the applied dose (RO).

Results obtained are as follows:- Example No F(0-16 hours)X 108 Mol cm-2 hour-1 n RQ (%) 1 2.6+0.5 8 24% 3 1.4+0.3 20 14% 4 ca 1.6 4 13% 5 ca 2.6 4 21% 13 1.3+0.01 12 12% 14 1.7l0.7 8 12% 17 ca 1.2 4 15% 18 ca 1.7 4 25% 20 ca 1.3 4 12% 25 1.6 # 0.6 8 13% The examples are listed hereinafter.

in vivo trials may be effected, e.g. including a comparative oral and percutaneous administration of the pharmacologically active agent in a cross-over study in a healthy subject.

In one study 480 mg of a microemulsion in the form of a gel as described in Example 1 containing 40 mg of active agent, tizanidine, was applied behind the ear, or a tablet containing 4 mg tizanidine, was administered orally.

The urine was collected over 72 hours and the amount of unchanged active agent and corresponding two metabolites were measured separately.

The results obtained were as follows:- unchanged drug after unchanged drug after Period after oral administration percutaneous adminiadministration [ g/hr] stration g/hr] 0-2 3.08 0.03 2-4 1.61 1.01 4-6 0.53 1.81 6-8 0.24 1.33 8-12 0.04 3.36 12-24 4.16 24-36 2.54 36-48 1.57 48-60 1.10 60-72 1.07 Cumulative % absorption oral percutaneous of tizanidine 0.28% 0.37% of Metabolite A 2.5 % 0.4 % of Metabolite B 1.1 % 0.16% The above results confirm the significant percutaneous absorption obtained in the in vitro tests, and indicate a sustained-release effect. Additionally the relatively lower amount of metabolite found indicates a significantly lower first pass effect.

100 mg of the clemastine composition of Example 3 (containing 10 mg clemastine) is applied behind the ear of 2 or 3 subjects (age 18 to 38 years) corresponding to an amount of active agent of 10 mg of clemastine.

The amount of active agent in the urine is determined according to the principles of R.Tham. Arzneim. Forsch. (1978) 28(1), 1017.

Period after active agent in administration urine \jLg/hrj Subjects hours 0-6 ~ 3 6-8 0.486 + 0.164 3 8-12 0.890i0.384 3 12-24 1.042 f 0.621 3 24-36 1.101j0.422 3 36-48 1.469 c 0.455 3 48-60 0.504 + 0.21 1 2 60-72 0.231 j0.05 2 % Cumulative elimination of unchanged drug 0.664 i 0.183 In comparison 2 mg of clemastine given orally over 72 hours yield 7.10% + 0.46% of the unchanged drug in the urine.

The results show an excellent effect with the maximum concentration in the urine occurring 36 hours after administration and a resorption quota of about 10% of the clemastine topically administered.

As indicated by the above results the microemulsions of the present invention may produce systemic action of the pharmacologically active agent. In pular we have surprisingly found that topical administration of tizanidine is feasible.

The present invention according provides a topical pharmaceutical composition containing tizanidine as active agent. In another aspect the present invention provides a method of topically administering tizanidine to a subject in need of such treatment.

The penetration rate observed may thus be at least in the order of 1 to 3 X 10-8 Mole cm-2 hour-1 to produce a systemic action and in the order of about 1 X 10-9 Mole cm-2 hour-1 to produce local action in the deeper dermal layers and the concentration of pharmacologically active agent in the microemuision may be chosen accordingly.

The amount of pharmacologically active agent to be administered in the microemulsions of the present invention will depend inter alia on the penetration rate of the pharmacologically active agent observed in the in vitro or in vivo tests, the potency of the active agent, the size of the skin area treated with the microemulsion, the part of the body treated and the duration of action required. In general a suitable daily dose is about from 5 to 20 times the dose effective in oral administration, and the dose may be increased if longer duration than 1 day is required.

In general a suitable application area is from about 1 to about 40 square centimeters. The microemulsions of the invention may be applied in conventional manner.

In the case of liquid preparations, the microemulsion can be applied for example from a plexiglass container in contact with e.g. the upper arm, or from a plaster soaked with the microemulsion placed e.g. behind the ear. In the case of semi-solid microgels these may be rubbed in the skin.

For example in the case of tizanidine and clemastine a suitable single dose is from 10 to 50 mg, and this may last for up to 3 days. The microemulsions of the invention may be used for the same indication that other forms of the pharmaceutically active agents are used for, e.g.

clemastine as an anti-histamine agent, and tizanidine as myotonolytic, anti-depressant or minor tranquillizer.

The microemulsions of the invention may enhance the penetration of the pharmacologically active agent which is accumulated in the horny layer of the epidermis. A depot effect may then result whereupon the pharmacologically active agent slowly passes into the systemic circulation without inactivation by the liver resulting in a longlasting concentration of active agent in the blood (retard effect). The blood concentration achieved by percutaneous delivery may be characterized by the absence of an initial drug concentration blood peak in contrast to oral administration. Side effects may be minimized. Additionally the accumulated pharmacologically active agent in the horny layer may provide a local effect if the pharmacologically active agent is locally active.

The microemulsions of the invention may in general possess significant other advantages over macroemulsions. For example they may in general be thermodynamically stable, and show little or no coalescene. In general the microemulsions of the invention have good spreading properties on the skin surface. They don't in general stick to the surface of the skin but may be easily rubbed in. They may leave little greasy feeling behind and may be washed off with water if desired. The skin may not be significantly dehydrated as the single water-containing phase may be easily available to the sl < in.

The following Examples illustrate the invention: Polyoxyethylene-(10)-oleyl ether is for example either BRIJ 97 having an HLB value of 12.4 available from Atlas, Essen, W. Germany, or VOLPO 10 having an HLB value of 12.4 available from Croda, Humberside, UK.

Polyethylene glycol glycerol fatty acid ester is for example brand Labrafil M 1 944 S available from Gatte-fosse, Boulogne, France.

Hexyllaurate is for example brand CETIOL A, available from Henkel, Düsseldorf.

Polyethyleneglycol-(7)-glyceryl cocoate is for example brand CETIOL HE available from Henkel.

Lactic acid is a 90% pure aqueous solution Colladerm 350 is a zinc salt of highly purified collagen-derived cosmetic medium molecular weight polypeptide available from Stepan Chemical Company, Northfield, Ill, USA.

Lauryl lactate is for example brand Ceraphyl 31, and myristyl lactate is for example brand Ceraphyl 50 from Van Dyk, Belleville, N.J., USA.

Further details on these products can be obtained from Fiedler H.P. Lexikon der Hilfsstoffe fUr Pharmazie, Kosmetik und angrenzende Chemie, 2nd Edition, Editor Cantor, the contents of which are hereby incorporated by reference, or their suppliers.

EXAMPLE ONE: Tizanidine micro gel 500 g of a mixture having the following compo sition :- Per cent Vizanidine 8.2 Isopropyl laurate 20.5 Polyoxyethylene (10) oleyl ether 20.5 (Brij 97) Dodecanol 6.5 Water 41.0 Lactic acid 3.3 are made and warmed by a water bath at about 90'C. The mixture is allowed to cool to room temperature by cooling the water 1"C per minute As the mixture is cooled various different phases are observed as follows:- Phase Temperature Milky macro-emulsion 92-72"C Transitional light cloudy 72-70"C phase Microemulsion transparent phase 70-66"C Transitional light cloudy 66-63"C phase Microemulsion transparent phase 63-51"C Transitional light cloudy phase 51-46"C Microemulsion transparent phase 46 'room temperature The cooled gel is filled into metal tubes.

Active agent dist, Additional Example ingredient Org. Solvent Co-Emulfifier Emulsifier water excipients No. % a b % c % % 2 1 1% Hexyllaurate 23% Poly(7)ehyl- 26% Polyoxyethylene- 20% 29.7% anhydrous 0.3% ene-glycol 10-oleyl ether acetio acid glyceryl-co- **A coete"C 3 2 10% Hexyllaurate 10% Poly(7)ehyl- 20% Polyoxyethylene- 20% 38.5% anhydrous 1.5% ene-glycol 10-oleyl ether acetic acid glyceryl-co- **A coete"C 4 3 8.2% 2,6,10,15,19,23- 20.5% Dodecanol 6.5% Polyoxyethylene- 20.5% 40,6% lactic acid 3.7% Hexamethyl-te- 10-oleyl ether 90% trecosane **A 5 3 8.2% isopropylmylri- 20.5% Dodecanol 6.% Polyoxyethylene- 20.5% 40,6% lactie acid 3.7% state 10-oleyl ether 90% **A 6 3 8.2% isopropylmyri- 20.5% Tetradecanol 6.5% Polyoxyethylene- 20.5% 34.6% lactie acid 3.7% state 10-oleyl ether 90%, Colla **A 7 4 8.3% isopropyl- 20.5% Dodecanol 6.5% Polyoxyethylene- 20.5% 41.3% lactie acid 2.9% laurate 10-oleyl ether 90% **A Active agent dist, Additional Example ingredient Org. Solvent Co-Emulfifier Emulsifier water excipients No. % a b % c % % 8 5 8.3% isopropyl 20.6% Dodecanol 6.5% Polyoxyethlyene- 20.6% 41.2% lactie acid 2.7% laurate 10-oleyl ether acid 90% **B 9 1 1.0% isoproyl 21.0% Dodecanol 7.0% Polyoxyethlyene- 18.0% 53.7% lacie acid 0.3% laurate 10-oleyl ether acid 90% **A 10 6 0.5% 2,6,10,15,19, 20.5% Dodecanol 6.5% Polyoxyethlyene- 21.0% 26.0% Polyethyl- 25.0% 23-Hexamethyl- 10-oleyl ether englycol tetraccsane **B 400 11 7 0.2% 2,6,10,15,19, 20.5% Dodecanol 8.8% Polyoxyethlyene- 20.5% 50.0% 23-Hexamethyl- 10-oleyl ether tetraccsane **B 12 8 0.1% isopropyl 22.5% Dodecanol 8.0% Polyoxyethlyene- 22.5% 46.9% laurate 10-oleyl ether **A 13 3 8.2% 2,6,10,15,19, 20.5% Dodecanol 6.5% Polyoxyethlyene- 20.5% 41.0% lactio 3.3% 23-Hexamethyl- 10-oleyl ether acid 90% tetraccsane **B 14 3 8.2% isopropyl 20.5% Dodecanol 6.5% Polyoxyethlyene- 20.5% 41.0% lactice 3.3% laurate 10-oleyl ether acid 90% **B Active agent dist, Additional Example ingredient Org.Solvent Co-Emulfifier Emulsifier water excipients No. % a b % c % % 15 3 8.2% Lauryllactate 20.5% Tetradecanol 6.5% Polyoxyethylene- 20.5% 41.0% lactic acid 3.3% 10-olsyl ether 90% **B or A 16 3 8.2% Myristyllactate 20.5% Tetradecanol 8.0% Polyoxyethylene- 20.5% 39.5% lactic acid 3.3% 10-olsyl ether 90% **A 17 4 8.3% Isopropyl 20.5% Dodecanol 6.5% Polyoxyethylene- 20.6% 41.3% lactic acid 2.9% laurate 10-olsyl ether 90% **B 18 5 8.3% Isoproyl 20.6% dodecanol 6.6% Polyoxyethylene- 20.6% 41.2% lactic acid 2.7% laurate 10-olsyl ether 90% **B 19 2 10% Isopropyl 20.5% Propylene- 10% Polyoxyethylene- 20.5% 35.6% lactic acid 3.4% myristete glycol mono 10-olsyl ether 90% laurate **B 20 3 8.2% Polyethylenegly- 20.5% Dodecanol 6.5% Polyoxyethylene- 20.5% 41.0% lactic acid 3.3% colglyceryl- 10-olsyl ether 90% fatty acié **B ester "D 21 9 4.0% Hexyllaurate 13.0% Poly(7)ethyl- 26.0%Polyoxyethylene- 10.0% 16.0% Propylen- 6.0% ene-glycol- 10-olsyl ether glycol glycerylcoco- **A Isopropanol 25.0% ate **C Active agent dist, Additional Example ingredient Org. Solvent Co-Emulfifier Emulsifier water excipients No. % a b % c % % 22 2 10% Propylene gly- 13% Poly(7)ethyl- 26% Polyoxyethylene- 20% 31% col mono-laurate ene-glycol-gly- 10-oleyl ather cerylcoocate **A **C 23 2 10% Propylene gly- 13% Poly(7)ethyl- 26% Polyoxyethylene- 20% 16% Alcohol 15% col mono-laurate ene-glycol-gly- 10-oleyl ather (69%) cerylcoocate **A **C 24 3 8.2% Isopropyl myristate 20.5%Dodecanol 8% Polyoxyethylene- 20.5% 39.1% lactic acid 3.7% 10-oleyl ather 90% **A 25 3 8.2% 2,6,10,15,19. 20.5% Dodacanol 8.5% Polyoxyethylene- 20.5% 41% lactic acid 3.3% 23-haxamethyl- 10-oleyl ather 90% tetracosane **A "Table of pharmacologically active agents 1. (E)-N-methyl-N-( 1 -naphthylmethyl)-3-phenyl-propen-2-ylamine.

2. (+)-1-methyl-2-[2-( & methyl-p-chlorodiphenyl-methoxy)-ethyl]-pyrrolidine.

3.5-chloro-4(2-imidazolin-2-ylamino)-2,1,3-benzothia-diazole.

4. 4-(1 -methyl-4-piperidylidene)-4H-benzo[4,5]cyclohepta[1,2-b]thiophen-1 H)-one.

5,4-(1-methyl-4-piperidylidene)-9.10-dihydro-4H-benzo-(4,5)-cyclohepta-(1,2-b)-thiophene.

6. Griseofulvin.

7. Fluocinolone acetonide.

8. Triamcinolone acetonide.

9. 14-O-[5-(2-amino-1,3,4-triazsolyl)thioacetyl]-dihydro-mutiline, also known as 1 4-[5-amino-4H- I , 2,4-triazol-3-yl)-thio-acetoxy]- 1 4-deoxy- 1 9, 20-dihydromutilin.

"Table of commercial products A BRIJ 97 HLB value 12.4 (ATLAS) B VOLPO 10 HLB value 12.4 (CRODA) C CETIOL HE (HENKEL) D LAFABRIL 19445 (GATTEFOSSE) Colladerm 350: A solution of a Zn salt of a highly purified cosmetic polypeptide of collagen (STEPHAN CHEMICAL COMPANY).

Claims (51)

1. A skin penetration pharmaceutical composition incorporating a skin-penetrable pharmacologically active agent, wherein the composition is in the form of a microemulsion formed from skin compatible excipients.
2. A composition as claimed in claim 1 wherein the composition is in the form of a microgel.
3. A composition as claimed in claim 1 or 2 wherein the active agent is a difficultly skinpenetrable active agent.
4. A composition as claimed in claim 3 comprising from 5 to 30% by weight of a waterimmiscible skin compatible solvent.
5. A composition as claimed in any preceeding claim containing from 4 to 30% by weight of a skin compatible emulsifier.
6. A composition as claimed in any preceeding claim comprising 10 to 30% by weight of a skin compatible co-emulsifier.
7. A composition as claimed in any preceding claim comprising 15 to 55% by weight of water.
8. A composition as claimed in any preceeding claim containing 0.01 to 15% by weight of skin-penetrable pharmacologically active agent.
9. A composition as claimed in claim 8 containing from 5 to 15% by weight of skinpenetrable pharmacologically active agent.
10. A composition as claimed in any preceeding claim containing a skin compatible ester of an aliphatic (C3,s) alcohol with an aliphatic (Cl022) carboxylic acid.
11. A composition as claimed in claim 10 wherein the ester is chosen from isopropyl laurate, hexyl laurate, decyl laurate, isopropyl myristate and lauryl myristate.
12, A composition as claimed in claim 10 wherein the ester is isopropyl laurate, hexyl laurate or isopropyl myristate.
13, A composition as claimed in claim 10 wherein the ester is hexyl laurate.
14. A composition as claimed in any preceding claim containing a skin compatible hydrocarbon having a straight carbon (C12 32) chain substituted by from 6 to 16 methyl groups and having up to 6 double bonds.
15. A composition as claimed in claim 14 containing squalane.
16. A composition as claimed in any preceeding claim containing a skin compatible monoester of ethylene glycol or propylene glycol with an aliphatic (C622) carboxylic acid.
17 A composition as claimed in claim 18 wherein the ester is propylene glycol monolaurate or propylene glycol monomyristate.
18. A composition as claimed in any preceeding claim wherein the ester is a skin compatible ester of an aliphatic (C,222) alcohol with lactic acid.
19. A composition as claimed in claim 18 wherein the ester is myristyl lactate or lauryl lactate.
20. A composition as claimed in any preceeding claim containing a skin compatible aliphatic (C,222) alcohol.
21. A composition as claimed in claim 20 wherein the alcohol is dodecanol, tetradecanol, oleyl alcohol, 2-hexyldecanol or 2-octyldecanol.
22. A composition as claimed in claim 20 wherein the alcohol is dodecanol.
23. A composition as claimed in any preceeding claim containing a skin compatible ester of a poly(2-7)ethylene glycol glycerol ether having at least one free hydroxyl group and an aliphatic (C622) carboxylic acid.
24. A composition as claimed in claim 23 wherein the ester is poly(7)ethylene glycol glyceryl cocoate.
25. A composition as claimed in any preceeding claim containing a skin compatible mono or diester of glycerol with an aliphatic (C622) carboxylic acid.
26. A composition as claimed in any preceeding claim containing a skin compatible ester having at least one hydroxyl group of a poly(2-10)glycerol with an aliphatic (C622) carboxylic acid.
27. A composition as claimed in any preceeding claim containing a skin compatible monoether of a polyethylene-glycol with an aliphatic (C12-18) alcohol having an HLB value of from 10 to 18.
28. A composition as claimed in claim 27 wherein the mono ether is polyoxyethylene(10)oleyl ether.
29. A composition as claimed in any preceeding claim containing a skin compatible ester of an aliphatic (C6 22) carboxylic acid with a) a polyethylene glycol b) a saccharose c) a sorbitan or d) a polyethylene glycol sorbitan ether, the ester having an HLB value of from 10 to 18.
30. A composition according to any preceeding claim containing as active agent (E)-N methyl-6, 6-dimethyl-N-(naphthylmethyl)hept-2-en-4-inyl- 1-amine, naftifin, ketotifen, pizotifen, griseofulvin, fluocinolone acetonidie, triamcinolone acetonide, 1 4-0-[5-(2-amino-1 ,3,4-triazoly.
th ioacetyll-d ihydro-m utiline, or proquazone.
31. A composition according to any preceeding claim containing as active agent clemastine.
32. A composition according to any preceeding claim containing as active agent tizanidine.
33. A composition according to claim 30 containing 1 4-0-[5-(2-amino-1 ,3,4-triazolyl)thioa- cetyll-dihydro-m utiline.
34. A composition according to claim 31 or 33 containing hexyl laurate, poly(7)ethylene glycol glyceryl cocoate and polyoxyethylene(1 0)oleyl ether.
35. A composition according to claim 32 containing 6 to 10% of tizanidine, 15 to 25% of water-immisicible organic solvent, 15 to 25% of emulsifier, 5 to 10% of co-emulsifier, and 30 to 35% of water.
36. A composition according to claim 35 containing isopropyl laurate, polyoxyethylene(lo)oleyl ether and dodecanol.
37. A pharmaceutical composition in the form of a microemulsion, substantially as hereinbefore described with reference to any one of the Examples.
38. A process for the production of a skin-penetrable pharmaceutical composition which comprises forming a microemulsion from water and a skin-penetrable pharmacologically active agent and skin compatible excipients capable of functioning as a water-immiscible organic solvent, an emulsifier and a co-emulsifier.
39. A process according to claim 38 wherein the skin-penetrable pharmacologically active agent, water-immiscible organic solvent and emulsifier are heated to a maximum of 100 C to form an emulsion and then cooled to form a microemulsion.
40. A process for the production of a composition as defined in claim 1 substantially as hereinbefore described with reference to the Examples.
41. A pharmaceutical composition whenever produced by a process according to claim 38, 39 or 40.
42. A method of enhancing the penetration of a skin-penetrable pharmacologically active agent through the skin which comprises applying the active agent to the skin in the form of a microemulsion consisting of skin compatible excipients.
43. A method according to claim 42 wherein the active agent is applied in the form of a microemulsion as defined in any one of claims 1 to 37.
44. Use of a microemulsion consisting of skin compatible excipients to administer percutaneously a skin-penetrable pharmacologically active agent.
45. Use according to claim 44 wherein the active agent is tizanidine.
46. Use according to claim 44 wherein the active agent is clemastine.
47. A microemulsion comprising an active agent chosen from (E)-N-methyl-6,6-dimethyl-N (naphthylmethyl)hept-2-en-4-inyl- 1 -amine, naftifin, ketotifen, pizotifen, griseofulvin, fluocinolane acetonide, triamcinolone acetonide. 14-O-[5-(2-amino-1,3,4-triazolyl)thioacetyl]-dihydro-mutiline.
or proquazone.
48. A microemulsion comprising clemastine or tizanidine.
49. A method of administering tizanidine by topical administration.
50. A topical pharmaceutical composition comprising tizanidine.
51. A semi-solid pharmaceutical composition comprising tizanidine.
GB8209940A 1981-04-06 1982-04-02 Topical pharmaceutical compositions Expired GB2098865B (en)

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Cited By (43)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2128087A (en) * 1982-10-07 1984-04-26 Ciba Geigy Ag Topically administrable anti-inflammatory pharmaceutical compositions
GB2141025A (en) * 1983-05-20 1984-12-12 Nitto Electric Ind Co Compositions for percutaneous administration
EP0226337A1 (en) 1985-11-15 1987-06-24 Unilever N.V. Skin moisturizing microemulsions
US4719239A (en) * 1984-02-23 1988-01-12 Muller Bernd W W Pharmaceutical multicomponent systems and method of preparing same
GB2211408A (en) * 1987-10-28 1989-07-05 Nippon Shinyaku Co Ltd Drug carrier containing fatty emulsion
US5149719A (en) * 1990-04-27 1992-09-22 Minnesota Mining And Manufacturing Company Composition for transdermal penetration of medicaments
WO1992018147A1 (en) * 1991-04-19 1992-10-29 Affinity Biotech, Inc. Convertible microemulsion formulations
WO1993011798A1 (en) * 1991-12-16 1993-06-24 Alza Corporation Improved formulations with hydrophobic permeation enhancers
WO1994008610A1 (en) * 1992-10-16 1994-04-28 Smithkline Beecham Corporation Pharmaceutical emulsion compositions
US5342625A (en) * 1988-09-16 1994-08-30 Sandoz Ltd. Pharmaceutical compositions comprising cyclosporins
WO1994019000A1 (en) * 1993-02-17 1994-09-01 Smithkline Beecham Corporation Microemulsions containing pharmaceutical compositions
US5364628A (en) * 1985-05-31 1994-11-15 Sandoz Ltd. Pharmaceutical compositions
US5629019A (en) * 1992-02-27 1997-05-13 Alza Corporation Formulations with hydrophobic permeation enhancers
US5639724A (en) * 1984-07-24 1997-06-17 Sandoz Ltd. Cyclosporin galenic forms
US5681849A (en) * 1991-05-20 1997-10-28 Novartis Ag Ltd. Pharmaceutical composition for topical applications
US5688761A (en) * 1991-04-19 1997-11-18 Lds Technologies, Inc. Convertible microemulsion formulations
US5741512A (en) * 1988-09-16 1998-04-21 Novartis Corporation Pharmaceutical compositions comprising cyclosporins
US5814305A (en) * 1991-03-08 1998-09-29 Novartis Ag Use of hydrophilic penetration agents in dermatological compositions for the treatment of onychomycoses, and corresponding compositions
US5945398A (en) * 1997-09-08 1999-08-31 Panacea Biotec Limited Pharmaceutical compositions containing cyclosporin
DE3805744C2 (en) * 1987-03-04 1999-09-23 Novartis Ag Phenylcarbamate to inhibit acetylcholinesterase
US5958876A (en) * 1996-06-19 1999-09-28 Novartis Ag Cyclosporin-containing pharmaceutical compositions
US6005001A (en) * 1991-05-20 1999-12-21 Novartis Ag (Formerly Sandoz Ag) Pharmaceutical composition
US6008191A (en) * 1997-09-08 1999-12-28 Panacea Biotec Limited Pharmaceutical compositions containing cyclosporin
US6007840A (en) * 1988-09-16 1999-12-28 Novartis Ag Pharmaceutical compositions comprising cyclosporins
WO2000033862A1 (en) 1998-12-11 2000-06-15 Pharmasolutions, Inc. Self-emulsifying compositions for drugs poorly soluble in water
US6165498A (en) * 1994-12-02 2000-12-26 Hexal Ag Transdermal preparation containing a loratidine metabolite with antihistaminic activity
US6187747B1 (en) 1997-09-08 2001-02-13 Panacea Biotech Limited Pharmaceutical composition comprising cyclosporin
US6258808B1 (en) 1991-06-27 2001-07-10 Novartis Ag Pharmaceutical composition
US6294192B1 (en) * 1999-02-26 2001-09-25 Lipocine, Inc. Triglyceride-free compositions and methods for improved delivery of hydrophobic therapeutic agents
US6346511B1 (en) 1997-09-08 2002-02-12 Panacea Biotec Limited Pharmaceutical composition comprising cyclosporin
US6391282B1 (en) * 1997-11-10 2002-05-21 Flemington Pharmaceutical Corp. Antihistamine sprays and ointments for relief of delayed contact dermatitis
US6420355B2 (en) 1992-09-25 2002-07-16 Novartis Ag Pharmaceutical compositions containing cyclosporins
US6475519B1 (en) 1997-01-30 2002-11-05 Novartis Ag Oil-free pharmaceutical compositions containing cyclosporin A
US6486124B2 (en) 1994-11-03 2002-11-26 Novartis Ag Cyclosporin compositions and process therefor
US6582718B2 (en) 1992-05-13 2003-06-24 Novartis Ag Cyclosporin compositions
US6951841B2 (en) 1995-11-29 2005-10-04 Novartis Ag Pharmaceutical compositions of macrolides or cyclosporine with a polyethoxylated saturated hydroxy-fatty acid
US7081445B2 (en) 1989-02-20 2006-07-25 Novartis Ag Cyclosporin galenic forms
US7374779B2 (en) * 1999-02-26 2008-05-20 Lipocine, Inc. Pharmaceutical formulations and systems for improved absorption and multistage release of active agents
US7740875B2 (en) 2004-10-08 2010-06-22 Mediquest Therapeutics, Inc. Organo-gel formulations for therapeutic applications
US7776349B2 (en) 2004-10-08 2010-08-17 Mediquest Therapeutics, Inc. Organo-gel formulations for therapeutic applications
US20120114741A1 (en) * 2003-06-20 2012-05-10 Afgin Pharma Llc Topical therapy for the treatment of migranes, muscle sprains, muscle spasms, spasticity and related conditions
US9757390B2 (en) 2010-11-30 2017-09-12 Lipocine Inc. High-strength testosterone undecanoate compositions
US9757389B2 (en) 2014-08-28 2017-09-12 Lipocine Inc. Bioavailable solid state (17-β)-hydroxy-4-androsten-3-one esters

Families Citing this family (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0667835B2 (en) * 1984-03-01 1994-08-31 エルテーエス・ローマン・テラピー‐ズユステーメ・ゲゼルシヤフト・ミツト・ベシユレンクテル・ハフツング・ウント・コンパニ・コマンデツト・ゲゼルシヤフト Pharmaceutical compositions
JPS61280426A (en) * 1985-06-04 1986-12-11 Ikeda Mohandou:Kk Anti-inflammatory and analgesic application agent
US4767625A (en) * 1985-09-02 1988-08-30 Kao Corporation Lamella type single phase liquid crystal composition and oil-base cosmetic compositions using the same
US4690774A (en) 1985-09-11 1987-09-01 Chesebrough Pond's Inc. Novel translucent water in oil emulsions
DE3908047C2 (en) * 1989-03-13 1992-04-09 Desitin Arzneimittel Gmbh, 2000 Hamburg, De
GB9111611D0 (en) * 1991-05-30 1991-07-24 Sandoz Ltd Liposomes
GB9126209D0 (en) * 1991-12-10 1992-02-12 Orion Yhtymae Oy Drug formulations for parenteral use
JP4227729B2 (en) 1997-10-29 2009-02-18 スミスクライン ビーチャム ピー エル シー Pleuromutilin derivatives as antibacterial substances
DE19825856A1 (en) * 1998-06-10 1999-12-16 Labtec Gmbh New topical formulation which includes active agent as liquid lipid nanoparticles in an oil-in-water emulsion
US7732404B2 (en) 1999-12-30 2010-06-08 Dexcel Ltd Pro-nanodispersion for the delivery of cyclosporin
DK1706128T3 (en) 2003-12-08 2010-10-04 Cpex Pharmaceuticals Inc Pharmaceutical compositions and methods for treating insulin-
US9308203B2 (en) * 2008-10-01 2016-04-12 Taiwan Biotech Co., Ltd. Pressure sensitive adhesive matrix device or system for the treatment or prevention of onychomycosis or tinea pedis
US20100173882A1 (en) 2009-01-08 2010-07-08 Lipocine, Inc. Steroidal Compositions
US9358241B2 (en) 2010-11-30 2016-06-07 Lipocine Inc. High-strength testosterone undecanoate compositions
US9931349B2 (en) 2016-04-01 2018-04-03 Therapeuticsmd, Inc. Steroid hormone pharmaceutical composition

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DK135454C (en) * 1972-05-09 1977-10-17 Wander Ag
GB1559811A (en) * 1975-07-28 1980-01-30 Sandoz Ltd Pharmaceutically active benzothiadiazole derivatives
DE2800062A1 (en) * 1977-01-14 1978-07-20 Sandoz Ag Benzofused heterocyclic ring five, their production and use

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GB2128087A (en) * 1982-10-07 1984-04-26 Ciba Geigy Ag Topically administrable anti-inflammatory pharmaceutical compositions
US4917886A (en) * 1982-10-07 1990-04-17 Ciba-Geigy Corporation Novel topically administrable pharmaceutical compositions
GB2141025A (en) * 1983-05-20 1984-12-12 Nitto Electric Ind Co Compositions for percutaneous administration
US4719239A (en) * 1984-02-23 1988-01-12 Muller Bernd W W Pharmaceutical multicomponent systems and method of preparing same
US5593686A (en) * 1984-03-01 1997-01-14 Sandoz Ltd. Pharmaceutical compositions
US5759997A (en) * 1984-07-24 1998-06-02 Novartis Ag Cyclosporin galenic forms
US5652212A (en) * 1984-07-24 1997-07-29 Cavanak; Thomas Cyclosporin galenic forms
US6306825B1 (en) 1984-07-24 2001-10-23 Novartis Ag Cyclosporin galenic forms
US6468968B2 (en) 1984-07-24 2002-10-22 Novartis Ag Cyclosporin galenic forms
US5977066A (en) * 1984-07-24 1999-11-02 Novartis Ag Cyclosporin galenic forms
US5639724A (en) * 1984-07-24 1997-06-17 Sandoz Ltd. Cyclosporin galenic forms
US5364628A (en) * 1985-05-31 1994-11-15 Sandoz Ltd. Pharmaceutical compositions
EP0226337A1 (en) 1985-11-15 1987-06-24 Unilever N.V. Skin moisturizing microemulsions
EP0226337B2 (en) 1985-11-15 1996-01-31 Unilever N.V. Skin moisturizing microemulsions
US4797273A (en) * 1985-11-15 1989-01-10 Elizabeth Arden Inc. Skin moisturizing microemulsions
US4797272A (en) * 1985-11-15 1989-01-10 Eli Lilly And Company Water-in-oil microemulsions for cosmetic uses
DE3805744C2 (en) * 1987-03-04 1999-09-23 Novartis Ag Phenylcarbamate to inhibit acetylcholinesterase
GB2211408B (en) * 1987-10-28 1992-04-15 Nippon Shinyaku Co Ltd Parenteral drug carriers comprising fatty emulsions
GB2211408A (en) * 1987-10-28 1989-07-05 Nippon Shinyaku Co Ltd Drug carrier containing fatty emulsion
US5342625A (en) * 1988-09-16 1994-08-30 Sandoz Ltd. Pharmaceutical compositions comprising cyclosporins
US5962014A (en) * 1988-09-16 1999-10-05 Novartis Ag Pharmaceutical compositions comprising cyclosporins
US5866159A (en) * 1988-09-16 1999-02-02 Novartis Ag Pharmaceutical compositions comprising cyclosporins
US7235248B2 (en) 1988-09-16 2007-06-26 Novartis Ag Pharmaceutical compositions comprising cyclosporins
US6007840A (en) * 1988-09-16 1999-12-28 Novartis Ag Pharmaceutical compositions comprising cyclosporins
US6024978A (en) * 1988-09-16 2000-02-15 Novartis Ag Pharmaceutical compositions comprising cyclosporins
US5916589A (en) * 1988-09-16 1999-06-29 Novartis Ag Pharmaceutical compositions comprising cyclosporins
US5741512A (en) * 1988-09-16 1998-04-21 Novartis Corporation Pharmaceutical compositions comprising cyclosporins
US5962017A (en) * 1988-09-16 1999-10-05 Novartis G Pharmaceutical compositions comprising cyclosporins
US7511014B2 (en) 1989-02-20 2009-03-31 Novartis Ag Cyclosporin galenic forms
US7081445B2 (en) 1989-02-20 2006-07-25 Novartis Ag Cyclosporin galenic forms
US5149719A (en) * 1990-04-27 1992-09-22 Minnesota Mining And Manufacturing Company Composition for transdermal penetration of medicaments
US6455592B1 (en) 1991-03-08 2002-09-24 Novartis Ag Use of hydrophilic penetration agents in dermatological compositions for the treatment of onychomycoses, and corresponding compositions
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US5814305A (en) * 1991-03-08 1998-09-29 Novartis Ag Use of hydrophilic penetration agents in dermatological compositions for the treatment of onychomycoses, and corresponding compositions
US5688761A (en) * 1991-04-19 1997-11-18 Lds Technologies, Inc. Convertible microemulsion formulations
US5633226A (en) * 1991-04-19 1997-05-27 Lds Technologies, Inc. Convertible microemulsion formulations
US5646109A (en) * 1991-04-19 1997-07-08 Lds Technologies, Inc. Convertible microemulsion formulations
US5444041A (en) * 1991-04-19 1995-08-22 Ibah, Inc. Convertible microemulsion formulations
WO1992018147A1 (en) * 1991-04-19 1992-10-29 Affinity Biotech, Inc. Convertible microemulsion formulations
US5681849A (en) * 1991-05-20 1997-10-28 Novartis Ag Ltd. Pharmaceutical composition for topical applications
US5856355A (en) * 1991-05-20 1999-01-05 Novartis Ag Pharmaceutical composition
US6121314A (en) * 1991-05-20 2000-09-19 Novartis Ag Pharmaceutical composition
US6005001A (en) * 1991-05-20 1999-12-21 Novartis Ag (Formerly Sandoz Ag) Pharmaceutical composition
US6844459B2 (en) 1991-06-27 2005-01-18 Novartis Ag Pharmaceutical Composition
US6258808B1 (en) 1991-06-27 2001-07-10 Novartis Ag Pharmaceutical composition
WO1993011798A1 (en) * 1991-12-16 1993-06-24 Alza Corporation Improved formulations with hydrophobic permeation enhancers
US5629019A (en) * 1992-02-27 1997-05-13 Alza Corporation Formulations with hydrophobic permeation enhancers
US6582718B2 (en) 1992-05-13 2003-06-24 Novartis Ag Cyclosporin compositions
US6262022B1 (en) 1992-06-25 2001-07-17 Novartis Ag Pharmaceutical compositions containing cyclosporin as the active agent
US6420355B2 (en) 1992-09-25 2002-07-16 Novartis Ag Pharmaceutical compositions containing cyclosporins
WO1994008610A1 (en) * 1992-10-16 1994-04-28 Smithkline Beecham Corporation Pharmaceutical emulsion compositions
WO1994019000A1 (en) * 1993-02-17 1994-09-01 Smithkline Beecham Corporation Microemulsions containing pharmaceutical compositions
US6486124B2 (en) 1994-11-03 2002-11-26 Novartis Ag Cyclosporin compositions and process therefor
US6395297B1 (en) 1994-12-01 2002-05-28 Hexal Ag Transdermal preparation contacting a loratidine metabolite with antihistaminic activity
US6165498A (en) * 1994-12-02 2000-12-26 Hexal Ag Transdermal preparation containing a loratidine metabolite with antihistaminic activity
US6951841B2 (en) 1995-11-29 2005-10-04 Novartis Ag Pharmaceutical compositions of macrolides or cyclosporine with a polyethoxylated saturated hydroxy-fatty acid
US5958876A (en) * 1996-06-19 1999-09-28 Novartis Ag Cyclosporin-containing pharmaceutical compositions
US6723339B2 (en) 1997-01-30 2004-04-20 Novartis Ag Oil-free pharmaceutical compositions containing cyclosporin A
US6475519B1 (en) 1997-01-30 2002-11-05 Novartis Ag Oil-free pharmaceutical compositions containing cyclosporin A
US6187747B1 (en) 1997-09-08 2001-02-13 Panacea Biotech Limited Pharmaceutical composition comprising cyclosporin
US6346511B1 (en) 1997-09-08 2002-02-12 Panacea Biotec Limited Pharmaceutical composition comprising cyclosporin
US6008191A (en) * 1997-09-08 1999-12-28 Panacea Biotec Limited Pharmaceutical compositions containing cyclosporin
US5945398A (en) * 1997-09-08 1999-08-31 Panacea Biotec Limited Pharmaceutical compositions containing cyclosporin
US6391282B1 (en) * 1997-11-10 2002-05-21 Flemington Pharmaceutical Corp. Antihistamine sprays and ointments for relief of delayed contact dermatitis
EP1135150A1 (en) * 1998-12-11 2001-09-26 Pharmasolutions, Inc. Self-emulsifying compositions for drugs poorly soluble in water
EP1135150A4 (en) * 1998-12-11 2006-05-17 Pharmasolutions Inc Self-emulsifying compositions for drugs poorly soluble in water
WO2000033862A1 (en) 1998-12-11 2000-06-15 Pharmasolutions, Inc. Self-emulsifying compositions for drugs poorly soluble in water
US6451339B2 (en) 1999-02-26 2002-09-17 Lipocine, Inc. Compositions and methods for improved delivery of hydrophobic agents
US6294192B1 (en) * 1999-02-26 2001-09-25 Lipocine, Inc. Triglyceride-free compositions and methods for improved delivery of hydrophobic therapeutic agents
US7374779B2 (en) * 1999-02-26 2008-05-20 Lipocine, Inc. Pharmaceutical formulations and systems for improved absorption and multistage release of active agents
US20120114741A1 (en) * 2003-06-20 2012-05-10 Afgin Pharma Llc Topical therapy for the treatment of migranes, muscle sprains, muscle spasms, spasticity and related conditions
US8883830B2 (en) * 2003-06-20 2014-11-11 Afgin Pharma LLC. Topical therapy for the treatment of migraines, muscle sprains, muscle spasms, spasticity and related conditions
US7740875B2 (en) 2004-10-08 2010-06-22 Mediquest Therapeutics, Inc. Organo-gel formulations for therapeutic applications
US7776349B2 (en) 2004-10-08 2010-08-17 Mediquest Therapeutics, Inc. Organo-gel formulations for therapeutic applications
US9949985B2 (en) 2010-11-30 2018-04-24 Lipocine Inc. High-strength testosterone undecanoate compositions
US9757390B2 (en) 2010-11-30 2017-09-12 Lipocine Inc. High-strength testosterone undecanoate compositions
US9943527B2 (en) 2010-11-30 2018-04-17 Lipocine Inc. High-strength testosterone undecanoate compositions
US9757389B2 (en) 2014-08-28 2017-09-12 Lipocine Inc. Bioavailable solid state (17-β)-hydroxy-4-androsten-3-one esters

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GB8408654D0 (en) 1984-05-16 grant
GB2148711A (en) 1985-06-05 application
CA1192496A (en) 1985-08-27 grant
FR2502951A1 (en) 1982-10-08 application
GB2148711B (en) 1985-12-18 grant
CA1192496A1 (en) grant
ES511169A0 (en) 1983-10-01 application
FI821123A (en) application
DE3212053A1 (en) 1982-10-21 application
FR2502951B1 (en) 1985-12-06 grant
ES8308698A1 (en) 1983-10-01 application
DK155882A (en) 1982-12-10 application
FI821123L (en) 1982-10-07 grant
FI821123D0 (en) grant
NL8201413A (en) 1982-11-01 application
GB2098865B (en) 1985-12-18 grant
FI821123A0 (en) 1982-03-31 application
ES511169D0 (en) grant

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