HK1161683A - Topical composition comprising a combination of at least two penetration enhancing agents - Google Patents

Description

Topical composition comprising a combination of at least two penetration enhancers

Technical Field

The present invention relates to novel compositions for enhancing the bioavailability of a drug, particularly for transdermal delivery of the drug. The composition according to the present invention comprises a mixture of at least two penetration enhancers and a non-aqueous solvent system. The invention also relates to liquid and solid formulations, such as gels, solutions, oils, emulsions, ointments, creams or sticks, comprising the novel compositions.

Suitable drugs are those which exhibit a lack or irregular bioavailability, for example lipophilic pharmaceutical compounds.

Background

Topical application of the medicament is preferably for the treatment of skin disorders. The reason is that, at least theoretically, it minimizes systemic exposure. This is effective as long as the drug is available through the skin, which requires that the drug be able to penetrate the barrier stratum corneum. Generally, the amount of drug that is available to the skin to access the interior of the barrier is only a fraction, on average, of about 1-3% of the administered dose. If the patients were all the same and no scar was present, it was no problem that 97-99% of the dose was left without the barrier. However, this is not the case. The permeability of intact skin differs at least 10-fold between patients. In addition, scarring and other irregularities of the skin are common, particularly in the skin that is subject to disease, plus differences in permeability of the skin between patients and in different areas. A 10-fold difference in drug permeability can result in a 10-fold difference in the dosage administered, and thus differences in therapeutic efficacy and side effects. For drugs with a narrow therapeutic window, or drugs with side effects, this lack of predictability may result in some patients receiving a dose less than effective, while other patients suffer from side effects.

Bioavailability is increased if the patient scars or otherwise loses the natural barrier function of the skin. If the bioavailability with intact barrier function is 1-3%, we can expect a 30-100 fold increase in bioavailability. A high increase in the amount of such drugs available would result in a 30-100 fold overdose.

There are several examples of how drugs act in this way. The solution to this problem is to increase the bioavailability to such an extent that the major part of the drug can be utilized. For example, if the bioavailability of a drug for intact barrier function is 50%, when the barrier function is defective, the maximum systemic exposure will be 2 times the expected administered dose.

US6121314A (NOVARTIS AG), US6005001A (NOVARTIS AG) and US5856355A (NOVARTIS AG) disclose "non-greasy topical solutions, emulsions or emulsions containing a compound of formula I as active agent and a lower alkanol, if desired with the addition of a solubilising agent or an oil phase such as isopropyl myristate, are also beneficial for delivery systems" for terbinafine delivery. These documents do not disclose or suggest the need for a combination of two enhancers to achieve improved permeation enhancing properties.

GB2146528A (hovells TREVOR) discloses compositions for application to the skin or scalp to promote hair growth, said compositions containing a humectant such as isopropyl myristate, an oil such as lanolin, an emulsifier such as a sorbitol ester, a preservative such as Nipastat, a hair follicle stimulant such as concretio silicea, and an enzyme catalyst such as carboxylase dehydrogenase derived from secretions of gastropods, particularly of macrocussis snails. The document does not contain any information about whether the positive effect of the penetration of isopropyl myristate is based on itself or in combination with other ingredients.

DE4038385A (ROECAR HOLDINGS NV) discloses improved bioavailability of sitosterol and its glycosides in the form of microemulsions with lecithin as carrier. Preferably, the microemulsion comprises isopropyl myristate as the emulsifier and isopropanol as the co-emulsifier. The microemulsion consists of 21-23% of lecithin, 15-16% of isopropanol and 7.0-7.5% of isopropyl myristate which are dispersed in water. When sitosterol and its glycoside exist in the form of microemulsion with lecithin as carrier, their bioavailability is improved. This document does not teach the use of two different permeation enhancers in an anhydrous formulation to enhance permeability.

US6503894B (UNIMED PHARMACEUTICAL INC), US2002183296A (DUDLEY ROBERT et al), US2003022877A (DUDLEY ROBERT), US2003139384A (DUDLEY, ROBERT) and US2003232072A (DUDLEY, ROBERT et al) describe as representatives of a large patent family a composition comprising an androgenic hormone or a synthetic steroid, C_1-4Alcohol, a penetration enhancer such as isopropyl myristate, and water, together with the gel base form a hydroalcoholic gel formulation. These documents disclose the effect of isopropyl myristate rather than the enhancement of penetration in combination with other agents. All of the formulations in these documents contain water.

WO 2005/025626A (PROCTER) discloses microcapsules for controlled release. The method of claim 4, wherein the stabilizing agent is selected from the group consisting of isopropyl myristate and several other agents. This document teaches the use of isopropyl myristate as a stabiliser in microcapsules.

WO 97/34644a (hoechst ag) discloses a formulation suitable for treating nail psoriasis comprising a substance effective against psoriasis, at least one spreading solvent including isopropyl myristate, at least one volatile solvent and a film forming agent. There is no teaching in this document of isopropyl myristate alone or in combination with other agents having permeation enhancing properties.

EP 1889609 a (meda ab) mentions isopropyl myristate as a lubricant in aqueous foam formulations containing fatty acids. This document does not teach that isopropyl myristate alone or in combination with other excipients has a permeation enhancing effect.

US 7425340 a (antares PHARMA IPL ag) discloses the use of ethanol as a penetration enhancer in the combination of a urea compound with an anticholinergic or antispasmodic agent. The document does not teach the usefulness and results of the combination of enhancers.

Effects of isopropyl myristate (IPM), isopropyl alcohol (IPA) and combinations of both in Brinkmann et al (britkmann, I, et al, effects of isopropyl myristate, isopropyl alcohol and combinations of both in the penetration of hydrocortisone through human Stratum Corneum (SC), skin pharmacology applications of skin physiology, 2003, vol.16, No.6, p.393-404.) the penetration of Hydrocortisone (HC) into human stratum corneum, the incorporation of IPM and IPA and combinations thereof into aqueous hydrophilic ointments (WHS), effects on HC permeability and accumulation of HC in human SC, and the effects of these substances on SC microstructure were studied. Differential scanning calorimetry and wide and small angle X-ray diffraction showed that IPM into SC caused the densification of bilayer lipids and the disorder of the keratin bound lipids. Both effects result in a reduction of the diffusion coefficient of HC in the SC and thus in a reduction of its permeability compared to HC in the WHS.

In another document, Brinkmann et al (BRINKMANN, I, et al, supra, which teaches the effects of glycerol, propylene glycol, isopropyl myristate and the combination of isopropanol and isopropyl myristate on human stratum corneum, pharmacology, 2005, vol.60, No.3, p.215-220) also investigated the effects of the combination of isopropanol and IPM on stratum corneum. These studies conclude that IPM alone reduces drug permeability in WHS formulations, while combined with isopropanol enhances permeability.

Gorukanti et al (GORUKANTI, SR., et al, transdermal administration of antiparkinson formulation benztropine I. Effect of excipients on skin penetration International journal of pharmacy (Int J Pharm.)1999, vol.192, No.2, p.159-172) showed that when formulations containing IPM and alcohols (ethanol, IPA and t-butanol) were used, the permeability of Benztropine (BZ) free base and its mesylate salt increased in mice. tert-butanol-IPM (2: 8) combination leads toThe highest BZ flux from the mesylate salt, 2016mg/cm²·h^-1Compared with water, the ratio is 100 times higher, and compared with various pure solvents, the ratio is 44-540 times higher. The observed increase in permeability of BZ mesylate by the alcohol-IPM mixture may be the result of a combination of reduced stratum corneum barrier function by the binary vehicle and moderate decomposition of BZ mesylate by the active epidermis/dermis.

Panchagnaula et al (Panchagnula, R., et al, a study of the transdermal delivery feasibility of paclitaxel in binary combination with ethanol and isopropyl myristate: solubilization, dispersion and lipid bilayer perturbation effects. pharmacology (Farmaco.), 2005, vol.60, No.11-12, p.894-9.) show the positive effect of IPM in combination with ethanol on permeability.

Cha et al (Cha, b.j., et al, enhanced skin penetration of a novel capsaicin derivative (DA-5018) in a binary excipient system of isopropyl myristate and ethoxydiglycol progress in pharmaceutical research (Arch Pharm Res.)2001, vol.24, No.3, p.2248.) shows that oleic acid has a negative effect on IPM-mediated penetration of DA-5018 through the skin.

Aranello et al investigated the effect of IPM and PG on the permeability of diclofenac through the skin (Aranello, a, et al, the effect of propylene glycol and isopropyl myristate on the in vitro transdermal penetration of diclofenac carboxyvinyl polymer gel european journal of pharmacy (Eur J Pharm Sci.)1999Jan, vol.7, No.2, p.129-35.) this paper did not investigate the combinations disclosed below in an anhydrous environment.

In another paper (larucea, E, et al, combined effect of oleic acid and propylene glycol in tenoxicam transdermal penetration and retention in skin Eur J pharma biopharmm.2001 Sep, vol.52, No.2, p.1139.) the effect of oleic acid and propylene glycol combinations on tenoxicam transdermal penetration was investigated, without teaching about the use of anhydrous formulations.

US 2007269393 a (wepfer scott) discloses a topical anesthetic formulation in the form of an anhydrous gel comprising benzyl alcohol, propylene glycol and ethoxydiglycol as a skin penetration enhancer.

US 2007179121 a (plott R t) relates to a composition comprising a corticosteroid, two or more penetration enhancers selected from the group consisting of diisopropyl adipate, dimethyl isosorbide, propylene glycol, 1, 2, 6-hexanetriol (1, 2, 6-hexapetriol) and benzyl alcohol.

US 2008153885A (MEADOWS CHEYNEY et al) relates to the preparation of a transdermal fluid comprising first and second skin permeation enhancers, an aprotic primary solvent, and a therapeutically effective amount of flunixin or a pharmaceutically acceptable salt thereof.

US 2008260655 a (TAMARKIN DOV et al) relates to a stable substantially anhydrous, alcohol-free, silicone-free, foamable carrier composition comprising petrolatum or mixtures thereof, at least one foaming agent, at least one volatile agent, with or without additional active agents.

US 5837289 a (GRASELA JOHN et al) describes two separate penetration enhancers for topical formulations, the first penetration enhancer preferably being a lecithin organogel formed with isopropyl palmitate or isopropyl myristate, and the second penetration enhancer preferably being a polyoxide (polyoxamer), preferably a polyoxyalkylene derivative of propylene glycol.

WO 2007/103555 a (nuvicance inc) relates to a topical composition for the treatment of skin diseases comprising two or more transdermal penetration agents having a synergistic effect but distinct biochemical pathways.

WO 2007/019224 a (watson laboririees inc) relates to a method and formulation for enhancing the permeability of the skin of a subject to a drug comprising administering a combination of lauryl alcohol and isopropyl myristate as a permeation enhancer for an area of skin to synergistically enhance the permeability of the drug.

WO 2007/066149 a (pharmakodex ltd) relates to compositions and dressing devices for the accurate and localized application of pharmaceutical compositions containing therapeutic agents to the skin.

Disclosure of Invention

Summary of The Invention

The above-mentioned problems have now been solved in many pharmaceutical products, and surprising effects have been achieved when the following conditions are present.

A general embodiment of the present invention is a topical composition comprising a drug, a combination of at least two penetration enhancers, wherein at least one penetration enhancer is selected from the group consisting of esters of saturated or unsaturated fatty acids with lower alcohols and iso-forms of alcohols; wherein the at least one penetration enhancer is selected from the group consisting of aliphatic diols and triols; wherein the components are present in a non-aqueous solvent system.

In said general embodiment, the drug is preferably a lipophilic drug, more preferably a lipophilic drug selected from the group consisting of an immunomodulator or immune response modifier, a tricyclic antidepressant, an analgesic, an anesthetic, an anti-inflammatory agent, a beta blocker, an antimicrobial agent and a Ca blocker, most preferably an immunomodulator, such as a toll-like receptor 7(TLR7) ligand, e.g. imiquimod.

Although the components used in the compositions of the present invention are standard components already used in topical products, the novel combination of these components has shown surprisingly good results in the transdermal delivery of drugs studied "in vitro".

Drawings

FIG. 1 shows the results of example 1;

FIG. 2 shows the results of example 2;

FIG. 3 shows the results of example 3;

FIG. 4 shows the results of example 5;

FIG. 5 shows the results of example 6; and

fig. 6 shows the results of example 7.

Detailed Description

The following description is the best mode presently contemplated for carrying out the present invention. This description is not to be taken in a limiting sense, but is made merely for the purpose of describing the general principles of the invention. The scope of the invention is to be determined with reference to the claims.

Before the present invention is described in detail, it is to be understood that this invention is not limited to the particular compounds or process steps described, as such compounds and processes may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting. It must be noted that, as used in the specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

Furthermore, the term "about" is used to indicate a deviation of +/-10% of a given value, preferably +/-5%, most preferably +/-2% of the value, where appropriate.

The term "non-aqueous" solvent system means that no water is added in the present invention. The terms "anhydrous" or "non-aqueous" do not exclude the presence of minute amounts of water in the starting materials, but it should be clear that no water is added to the composition.

A substance is considered lipophilic when it has lipid affinity and high lipid solubility. Lipophilicity is therefore a physicochemical property describing the partitioning equilibrium of solute molecules in water and immiscible organic solvents, which tend to be the latter.

Lipophilicity is generally expressed in terms of partitioning in water and water-insoluble solvents, LogP. The solvent most commonly used for drug delivery and development is 1-octanol. LogP refers to the logarithm of the partition coefficient P, defined as the ratio of the concentration of uncharged chemical species(s) in octanol divided by the concentration of uncharged chemical species in water. Lipophilic drugs suitable for the purposes of this embodiment are those having a LogP of at least about 1.5.

The present inventors have obtained a topical composition comprising a drug, a combination of at least two penetration enhancers, wherein at least one penetration enhancer is selected from the group consisting of esters of saturated or unsaturated fatty acids with lower alcohols and iso-forms of alcohols; wherein the at least one penetration enhancer is selected from the group consisting of aliphatic diols and triols; wherein the components are present in a non-aqueous solvent system.

The formulations of the present invention thus comprise a combination of at least two penetration enhancers and at least one non-aqueous solvent. The formulation may optionally include at least one solubility modifier, it being understood that the formulation includes excipients commonly used in formulations for topical use to make a suitable product.

A combination of permeation enhancers suitable for the performance of the present formulation as measured by drug delivery across a skin membrane, preferably a mixture of at least one permeation enhancer selected from the group consisting of esters of saturated or unsaturated fatty acids with lower alcohols or iso-forms of alcohols (e.g., isopropanol, isobutanol), and at least one permeation enhancer selected from the group consisting of fatty diols and triols. Non-limiting examples of ester-type penetration enhancers are methyl laurate, isopropyl myristate, isopropyl palmitate, butyl stearate, ethyl oleate, and diisopropyl adipate. Sorbitan esters of fatty acids and monoglycerides, as well as mono-, di-, and tri-unsaturated fatty acid esters, may also be used. Non-limiting examples of additional fatty diol and triol type penetration enhancers include ethylene glycol, propylene glycol, butylene glycol, hexylene glycol, and glycerol.

Pharmaceutical substances suitable for the novel formulations are preferably drugs which are lipophilic or soluble in a non-aqueous environment, preferably with a logP interval of about 1.5 to about 5.

Furthermore, the most preferred pharmaceutical substances are lipophilic compounds with high potency and/or toxicity having a small or narrow therapeutic window. Thus, the drug is preferably a lipophilic drug, more preferably a lipophilic drug selected from the group consisting of an immunomodulator or immune response modifier, a tricyclic antidepressant, an analgesic, an anesthetic, an anti-inflammatory agent, a beta blocker, an antimicrobial agent and a Ca blocker.

More preferably the medicament comprises an immunomodulatory compound, and according to one embodiment the immunomodulatory agent comprises a toll-like receptor 7(TLR7) ligand. Examples include, but are not limited to: imiquimod, amlodipine, nifedipine, felodipine and resiquimod.

One non-limiting example of an immunomodulatory compound is imiquimod.

The drug is present in an amount necessary to produce a pharmacological effect on the target tissue, the skin. According to one embodiment of the invention, the drug is present in an amount of about 0.01% to about 5% by weight based on the total weight of the composition. Preferably, as a result of the improved permeability achieved by the formulations of the present invention, the drug is present in a low amount, for example, in an amount of about 0.01% to about 1% by weight, based on the total weight of the composition.

According to one embodiment of the invention, in free combination with other embodiments, the alcohol is isopropanol or isobutanol.

According to further embodiments of the present invention, the penetration enhancer comprises isopropyl myristate and isopropyl alcohol.

According to one embodiment, the amount of the combination of penetration enhancers is from about 1% to about 99% based on the total weight of the composition. In liquid formulations, such as gels, creams, ointments or oily formulations or oils, the amount of penetration enhancer combination is preferably from about 50% to about 99% based on the total weight of the composition. In solid or semi-solid formulations, such as creams or sticks, the amount of penetration enhancer combination is preferably from about 5% to about 60% based on the total weight of the composition.

In one embodiment of the present invention, the ratio between the first and second penetration enhancers is from about 1: 10 to about 10: 1, preferably from about 1: 2 to about 2: 1.

Solvents or solvent mixtures suitable for the present formulation system are selected from the group of compounds, e.g. aromatic alcohols such as benzyl alcohol, esters of alpha-hydroxy acids such as, but not limited to, esters of short chain alcohols (having up to eight carbon atoms) with lactic acid or fatty acids. Other types of suitable solvents having similar solubility properties are represented by cyclohexanol, diacetone alcohol, ethylene glycol monomethyl ether, diethylene glycol monomethyl ether, ethylene glycol monoethyl ether, diethylene glycol monoethyl ether, methyl salicylate, benzoic acid, oleyl alcohol, and acetic acid. Short-chain fatty alcohols such as ethanol, propanol and isopropanol are also suitable. Preferably, the solvent is present in an amount of 1 to 80 wt.%, based on the total weight of the composition.

According to a preferred embodiment of the present invention, the non-aqueous solvent comprises at least one selected from the group consisting of aromatic alcohols, esters of aromatic alcohols with fatty acids, or esters of alpha-hydroxy acids with short chain alcohols (having up to eight carbon atoms). According to one non-limiting example, the presently preferred alcohol of the inventors is benzyl alcohol.

Preferably the non-aqueous solvent comprises at least one selected from the group consisting of cyclohexanol, diacetone alcohol, ethylene glycol monomethyl ether, diethylene glycol monomethyl ether, ethylene glycol monoethyl ether, diethylene glycol monoethyl ether, methyl salicylate, benzoic acid, oleyl alcohol and acetic acid. According to one non-limiting example, the ester presently preferred by the inventors is selected from lactate esters, and the solvent presently preferred is selected from methyl lactate, ethyl lactate, propyl lactate, and butyl lactate.

According to another embodiment, the solvent comprises at least one selected from the group consisting of short chain aliphatic alcohols of up to eight carbon atoms. Preferably, the solvent includes at least one selected from the group consisting of ethanol, propanol and isopropanol.

According to another embodiment, the solvent comprises at least one solvent selected from the group consisting of esters of alpha-hydroxy acids with short-chain alcohols (having up to eight carbon atoms).

According to any one of the above embodiments, the solvent or solvent combination is present in an amount of 1% to 80% by weight based on the total weight of the formulation.

The composition according to one embodiment of the present invention may further comprise a structuring agent. The topical composition may, for example, be diluted with inactive ingredients commonly used in topical products to impart texture and other physical properties. Non-limiting examples of such ingredients are mineral oil, soft white wax (soft white paraffin) and waxes (waxes), such as, but not limited to, palm wax.

The structuring agent preferably comprises at least one wax selected from the group consisting of soft white wax, paraffin oil, and wax, such as, but not limited to, palm wax, to increase the viscosity of the formulation. Alternatively or in combination therewith, the structuring agent may comprise a soluble or insoluble polymer. Examples of insoluble polymers are, for example, latex type polymers such as, but not limited to Eudragit(Evonik Industries)。

The composition also preferably includes a colorant. When applied to the skin, the colorant is useful for indicating the amount and distribution of the composition, so that the colored composition is easier to administer and apply uniformly. The skilled person will be able to select suitable colouring agents or pigments which are approved for use in topical pharmaceutical compositions.

The solvent desired for the present formulation may be selected based on solubility properties. The highly effective solvent in the present formulation, such as benzyl alcohol, can be replaced by other solvents having similar solubility parameters under the conditions involving hydrogen bonding, polarity and dispersion forces. Similar dissolution parameters mean a variation within ± 10%.

Solubility modifiers represented by carboxylic acids, including fatty acids, such as, but not limited to, caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid, behenic acid, lignoceric acid, myristoleic acid, palmitoleic acid, linoleic acid, linolenic acid and isostearic acid, oleic acid, benzoic acid, acetic acid, citric acid, oxalic acid, salicylic acid, ascorbic acid, and alpha-hydroxy acids such as glycolic acid, lactic acid, malic acid, and tartaric acid. The role of the solubility modifier is to adjust the solubility of the drug so that the formulation has the proper degree of saturation. According to any of the above embodiments, the composition may further comprise a solubility modifier in an amount of about 1% to about 60% by weight based on the total weight of the composition.

A non-limiting example of a presently preferred solubility modifier by the inventors is oleic acid.

A topical composition according to the invention may be formulated as a solution, gel, cream, ointment, oil or stick. A person skilled in the art of topical pharmaceutical preparations can easily formulate a solution, gel, cream, ointment, oil or stick within the scope of the claims without inventive work.

The composition can be made into stick. Sticks are well known and any known method for producing sticks with the present composition can be used. U.S. patent No.4,069,574(Krevald) discloses examples of methods that may be used, the complete disclosure of which is incorporated by reference in this application. An example of a suitable stick is disclosed in U.S. patent No.5,819,993 (wille), the complete disclosure of which is incorporated herein by reference.

When the composition is in the form of a stick, it is preferred that the total amount of penetration enhancer is from about 1 to 50% by weight, based on the total weight of the composition.

The improved permeability achieved by the present invention shows numerous advantages. For example, one advantage of the present invention is that the permeability of the drug is improved by the use of permeation enhancers and solvents that are approved for use with the drug. Another advantage of the present invention is that the invention will be easily understood by a person skilled in the art from a reading of the description, the claims and the non-limiting examples.

Examples

The invention will be more readily understood in connection with the following examples, which are intended to illustrate, but not limit the scope of the invention.

In vitro evaluation of the pharmaceutical formulations referred to in the examples below, the cell area was 0.63cm at 32 ℃ in a full thickness porcine ear skin membrane of approximately 900 μm thickness²The Bronaugh diffusing cells of (3) were subjected to the experiment. In example 4, the procedure was carried out using a Franz diffuser. The flow rate of the receptor medium (receptor medium flow) was set to 1.6ml/h, and a citrate buffer solution or a phosphate buffer solution containing a surfactant was used as the receptor medium.

Imiquimod (3- (2-methylpropyl) -3, 5, 8-triazacyclo [ 7.4.0.0)^2，6Tridec-1 (9), 2(6), 4, 7, 10, 12-hexane-7-amine) is an approved immune response modifier for the treatment of actinic keratosis, superficial basal cell carcinoma and external genital or condyloma, currently marketed under the trade name Aldara^TMAnd Beselna^TM. Imiquimod was chosen because it has been reported to have side effects ranging from local reactions such as redness, skinning, flaking, swelling, scabbing, itching/burning, to systemic effects such as fever, muscle pain, etc. Imiquimod was also chosen to exemplify the invention, as there is a commercial formulation (Aldara)^TM) For comparative experiments.

Example 1

The in vitro permeability of imiquimod from formulation A shown in Table 1 was determined and compared with that from commercially available Aldara^TMThe penetration of imiquimod was compared for a 5% cream (3M healthcare limited).

TABLE 1 composition of formulation A

The abbreviation "S" refers to solvent and "PE" refers to penetration enhancer.

Table 2 shows the experimental parameters of the in vitro experiments.

TABLE 2 Experimental parameters

The results in figure 1 show the average amount of Aldara permeated by imiquimod after 48 hours^TMHigher than preparation A, and the order of the skin penetration levels of both are the same. Imiquimod per cm²The average amount of penetration, n, is 7. Formulation a contained imiquimod, benzyl alcohol and propylene glycol.

Example 2

The in vitro permeability of imiquimod from formulation B shown in Table 3 was determined and compared with that from commercially available Aldara^TMThe imiquimod permeability of the 5% cream (3M healthcare limited) was compared.

TABLE 3 composition of formulation B

Abbreviations used: "S" solvent, "PE" penetration enhancer, "SM" solubility modifier.

Table 4 shows the experimental parameters of the in vitro experiments. TABLE 4 Experimental parameters

The results in FIG. 2 show the average amount of imiquimod permeated across using formulation B to Aldara^TMThe 5% cream was 45 times higher. FIG. 2 shows imiquimod per cm²The average amount of penetration, n, is 7. Formulation B comprised imiquimod, benzyl alcohol, propylene glycol, oleic acid, and isopropyl myristate.

The above results are compared with those of example 1, and it can be seen that when oleic acid and isopropyl myristate were added to the formulation, the permeability was significantly increased. For formulation B, the dose fraction of imiquimod penetration (dose fraction) after 48 hours was about 5% (w/w), whereas Aldara^TMThe 5% cream is only about 0.1% (w/w).

Example 3

The in vitro permeability of imiquimod from formulations C and D shown in Table 5 was determined and then compared with that from commercially available Aldara^TMThe penetration of imiquimod was compared for a 5% cream (3M healthcare limited).

TABLE 5 compositions of formulations C and D

Table 6 shows the experimental parameters of the in vitro experiments

TABLE 6 Experimental parameters

The results in figure 3 show that the average amount of imiquimod permeated through formulation D was 25-fold higher than the corresponding permeation from formulation C.

FIG. 3 shows imiquimod per cm²The average amount of penetration, formulation C is 7 and formulation D is 6, Aldara^TM5% of the cream is n-7. Formulation C contained imiquimod, benzyl alcohol, propylene glycol, formulation D contained imiquimod, benzyl alcohol, propylene glycol, and isopropyl myristate. These results show that the presence of isopropyl myristate and benzyl alcohol greatly enhanced the permeability of imiquimod. Imiquimod osmotic dose fraction formulation C and formulationD is 0.7% (w/w) and 37.5% (w/w), respectively, and Aldara^TMThe 5% cream penetrated a dose fraction below 0.1% (w/w).

Example 4

Both formulations, containing benzyl alcohol and isopropyl myristate, with and without propylene glycol, respectively, were tested for drug penetration through full thickness porcine ear skin in a Franz cell diffusion instrument. Table 7 shows the formulations.

TABLE 7 compositions of formulations D and E

The average fraction of imiquimod permeated from formulation D was 15.2%, while the fraction permeated from formulation E was only 1.0%. The results clearly show the importance of the presence of propylene glycol in the formulation according to the invention.

TABLE 8 Experimental parameters

Example 5

The solvent in the formulation may be selected based on solubility properties. The highly effective solvent in the present formulation, such as benzyl alcohol, can be replaced by other solvents having similar solubility properties under the conditions. In this example, benzyl alcohol was replaced with butyl lactate. Table 9 shows the compositions of formulations F and G.

TABLE 9 compositions of formulations F and G

Table 10 shows the experimental conditions

TABLE 10 in vitro experiments

Aldara^TMThe cream was used as a control in a skin penetration study that determined the amount of imiquimod present in the dermal layers. Prepared by F, G and Aldara^TMAfter 20 hours of treatment, the skin membrane was washed and the stratum corneum was removed. The resulting dermal tissue was used to determine the presence of imiquimod. The concentration of the formulations F and G in the dermal layer was 62. mu.g/ml and 59. mu.g/ml, respectively, as compared with commercial Aldara^TMOnly a tissue concentration of 7. mu.g/ml was obtained. Table 11 and figure 4 show the amount of imiquimod accumulated by permeation.

Imiquimod of formulations F and G was similar in permeability to skin, showing the possibility of replacing benzyl alcohol with other solvents based on criteria for solvent performance.

TABLE 11 accumulation of permeated imiquimod (ISM09199)

Example 6

In this example, the permeability of a composition containing two permeation enhancers and a solvent in combination with a wax was determined and compared to a commercial formulation of Aldara^TMA5% cream (3M healthcare Co., Ltd.) was compared. Table 12 shows the composition of the sticks.

TABLE 12 actual composition of sticks for limited dose experiments

Batches of	ISM08164
		Components	％(w/w)
Imiquimod	0.09
		Benzyl alcohol	34.27
Propylene glycol	14.68
		Myristic acid isopropyl ester	20.97
Palm wax	30.00
		Total amount% (w/w)	100.0

In the above permeation test, Aldara was used as the test composition^TMRecommended dose of (2) 10mg/cm²Full thickness pig ear skin was used as the membrane.

Figure 5 shows the average accumulated amount of permeated imiquimod.ISM08164 uses five cells, Aldara^TM5% of the cream used 4 cells. Error bars represent 95% confidence intervals. The novel formulation of the invention is administered in a total dose ratio of Aldara^TM50 times lower, but the mean amount of osmotic accumulation is higher than that of Aldara^TMAbout 5 times higher.

Example 7

The in vitro permeability of imiquimod from formulation H, shown in Table 13, was evaluated and compared to that from commercially available Aldara^TMThe penetration of imiquimod was compared for a 5% cream (3M healthcare limited).

TABLE 13 composition of formulation H

The following abbreviations were used: "S" solvent, "PE" penetration enhancer, "SM" solubility modifier.

Table 14 shows the experimental parameters of the in vitro experiments

TABLE 14 Experimental parameters

The results in FIG. 6 show the average amount of permeated imiquimod versus Aldara obtained using formulation H^TMThe 5% cream was more than 45 times higher. FIG. 6 shows imiquimod per cm²The average amount of penetration was n-5. Formulation H contained imiquimod, benzyl alcohol, propylene glycol, ethyl oleate, and isopropyl myristate.

Comparing the results of this experiment with those of example 1, it can be seen that the permeability is greatly increased when ethyl oleate and isopropyl myristate are added to the formulation. For formulation H, the permeated imidazole after 48 hoursThe quinocet dose fraction was about 40% (w/w), while Aldara^TMThe 5% cream is only about 0.1% (w/w).

While the claimed invention has been described in detail and with reference to specific embodiments thereof, it will be apparent to one skilled in the art that various changes and modifications can be made therein without departing from the spirit and scope thereof.

Claims (28)

1. A topical composition comprising a drug, a combination of at least two penetration enhancers, wherein at least one penetration enhancer is selected from the group consisting of esters of saturated or unsaturated fatty acids with lower alcohols and iso-forms of alcohols; wherein the at least one penetration enhancer is selected from the group consisting of aliphatic diols and triols; and wherein the components are present in a non-aqueous solvent system.

2. The composition of claim 1, wherein the drug is a lipophilic drug.

3. The composition of claim 2, wherein the drug is selected from the group consisting of an immunomodulator or immune response modifier, a tricyclic antidepressant, an analgesic, an anesthetic, an anti-inflammatory agent, a beta blocker, an antimicrobial agent and a Ca blocker.

4. The composition of claim 3, wherein the drug comprises an immunomodulatory compound.

5. The composition of claim 4, wherein the immunomodulatory compound comprises a toll-like receptor 7(TLR7) ligand.

6. The composition of claim 4, wherein the immunomodulatory compound is imiquimod.

7. The composition of claim 1, wherein the drug is present in an amount of about 0.01 to about 5% by weight based on the total weight of the composition.

8. The composition of claim 7, wherein the drug is present in an amount of about 0.01 to about 1% by weight based on the total weight of the composition.

9. The composition of claim 1, wherein the alcohol is isopropanol or isobutanol.

10. The composition of claim 1, wherein the penetration enhancer comprises isopropyl myristate and propylene glycol.

11. The composition of claim 1 wherein the amount of the penetration enhancer combination is from about 1 to about 99% by weight based on the total weight of the composition.

12. The composition of claim 11 wherein the amount of the penetration enhancer combination is from about 50 to about 99% by weight based on the total weight of the composition.

13. The composition of claim 11 wherein the amount of the penetration enhancer combination is from about 5 to 60% by weight based on the total weight of the composition.

14. The composition of claim 1 wherein the ratio between the first and second penetration enhancers is from about 1: 10 to about 10: 1.

15. The composition of claim 14 wherein the ratio between the first and second penetration enhancers is from about 1: 2 to about 2: 1.

16. The composition of claim 1, wherein the non-aqueous solvent comprises at least one selected from the group consisting of aromatic alcohols, esters of aromatic alcohols with fatty acids, or esters of alpha-hydroxy acids with short chain alcohols having up to eight carbon atoms.

17. The composition according to claim 1, wherein the non-aqueous solvent comprises at least one selected from the group consisting of cyclohexanol, diacetone alcohol, ethylene glycol monomethyl ether, diethylene glycol monomethyl ether, ethylene glycol monoethyl ether, diethylene glycol monoethyl ether, methyl salicylate, benzoic acid, oleyl alcohol, oleic acid, and acetic acid.

18. The composition of claim 1, wherein the solvent comprises at least one selected from the group consisting of short chain aliphatic alcohols having up to eight carbon atoms.

19. The composition of claim 18, wherein the solvent comprises at least one selected from the group consisting of ethanol, propanol, and isopropanol.

20. The composition of claim 1, wherein the solvent comprises at least one solvent selected from the group consisting of esters of alpha-hydroxy acids with short chain alcohols having up to eight carbon atoms.

21. The composition of claim 1, wherein the solvent or combination of solvents is present in an amount of 1 to 80% by weight based on the total weight of the formulation.

22. The composition of claim 1, further comprising a structurant.

23. The composition of claim 1, further comprising a non-solvent that dilutes the composition and creates texture.

24. The composition of claim 1, further comprising a colorant.

25. The composition of claim 22, wherein the structuring agent comprises at least one wax to increase the viscosity of the formulation, said wax being selected from the group consisting of soft white wax and paraffin oil.

26. The composition of claim 22, wherein the structuring agent comprises a soluble or insoluble polymer.

27. The composition of claim 1, further comprising a solubility modifier in an amount of about 1 to about 60% by weight based on the total weight of the composition.

28. A topical composition according to any preceding claim, in the form of a solution, gel, cream, ointment, oil or stick.