WO2004030665A1

WO2004030665A1 - Transparent gel composition, for the administration of diclofenac sodium through the skin

Info

Publication number: WO2004030665A1
Application number: PCT/GB2003/004398
Authority: WO
Inventors: Francisco Jose Evaristo Stefano
Original assignee: Thalas Group Incorporated; Paget, Hugh, Charles, Edward
Priority date: 2002-10-07
Filing date: 2003-10-07
Publication date: 2004-04-15
Also published as: AR036755A1; AU2003269266A1

Abstract

A transparent gel composition for the topical, local or systemic administration of diclofenac through the skin comprises diclofenac sodium in a concentration of 5% or higher and a mixture of oleyl alcohol and isopropyl alcohol in a ratio between 0.020 and 0.12. The composition also comprises pharmaceutically acceptable excipients. A procedure for the preparation of said composition is described.

Description

Transparent gel composition, for the administration of diclofenac sodium through the skin

The present invention relates to a transparent gel composition for the transder al administration of diclofenac.

DESCRIPTION OF THE PRIOR ART

In medical practice, several anti-inflammatory agents are used, which can be divided in two main groups: non-steroidal anti-inflammatory drugs (NSAIDs) and steroidal anti- inflammatory drugs. The anti-inflammatory compound diclofenac, that belongs to the first group, is one of most used pharmaceutical compounds all over the world.

This compound is administered "per os", via injection, or by rectal or topical administration, according to the circumstances. Nevertheless, when the diclofenac is administered orally, it usually develops several adverse side effects as, for example, severe gastrointestinal problems.

The advantages of the transdermal administration of drugs over other administration routes are well known. However, the permeation of the majority of drugs through the skin is not enough to provide suitable therapeutics levels in blood. The skin, particularly the stratum corneum, provides a barrier for the penetration of the majority of substances. In order to solve this problem, several alternatives have been proposed, most of them based on the use of a suitable penetration enhancer.

In comparison with the conventional routes of administration for potent drugs, transdermal administration offers important advantages, mainly because of its simplicity and because of its administration is not invasive. Additionally, this route reaches the circulating blood without the "first pass" through the digestive system and the liver, where, in many cases, a significant proportion of the drug is metabolised and inactivated.

In the prior art, there are several documents that disclose compositions for topical administration (gels, creams and ointments) that comprise variable concentrations of anti- inflammatory agents. Within them, the following can be highlighted: US 5,472,982, US 5,350,769, US 5,824,658, US 5,527,832, US 5,164,416, US 4,670,254, US 4,917,886, US 5,422,102, US 5,374,661, US 4,545,992, US 5,795,916 and JP 9208463.

However, all these documents are related to formulations whose effects are restricted to the application site and do not mention any general or systemic effect. Thus, the description of the uses in the documents mentioned above would be limited to the treatment of pain in the vicinity of the application site.

In particular, the transdermal administration of diclofenac, as well as the majority of the non-steroidal anti- inflammatories is limited because of the slow permeation rate that these compounds have through the skin. This limitation has been overcome in some cases, through the addition of the so called "permeation enhancers". However, the preparation of a diclofenac gel presents the disadvantage that, although the water solubility of diclofenac is approximately 1.5%, when the excipients of common use in this type of formulations are added, this compound tends to crystallise.

Therefore, the selection of the excipients in general and of the permeation enhancer in particular has a high relevance in the development of a transparent gel for the transdermal administration of diclofenac through the skin.

On the other hand, diclofenac sodium is dissolved with difficulty in water and an oily base and, for this reason, the preparations for external use that contain this compound are usually prepared as dispersions of diclofenac sodium. However, it is known that transdermal absorption is not good when the preparations are in a dispersion state. Therefore, in the literature, several techniques to dissolve diclofenac sodium using different additives have been described.

There are, for example, known preparations for external use, as oily ointments, which are characterised by the use of propyleneglycol, etc. as solubilizer agent to solve the problem of the insolubility of diclofenac sodium in oily bases (Japanese Patent Publication No. 59-33211) , gel preparations wherein there is a defined amount of alcohol used (Japanese Patent Publication No. 59-76013), and emulsions in which fatty acids and dialkyl esters of carboxylic acid are used (Japanese Patent Publication No. 64- 13020) . ^■ However, although in some of the ointments mentioned above, a better solubility for the diclofenac sodium is achieved, the transdermal absorption of said compound is not completely satisfactory. Likewise, in the case of the gels above mentioned, it is very difficult to control the amount of diclofenac sodium to be administrated. Additionally, for the correct use of some of them, it is necessary to cover the application site with a bandage or something similar to avoid the adhesion of the formulation to the clothes. Likewise, in the case of the preparations that use alcohol, diclofenac sodium crystallises because of the volatility of the alcohol while, at the same time and because of the contact of the alcohol with the skin during a long period of time, it is possible that they cause irritation.

The use of surfactants is not a satisfactory solution to improve the solubility of diclofenac either, since the use of them usually increases the incidence of irritation at the application site.

Several compounds have been proposed as permeation enhancers to be used in preparations for transdermal administration, the following being the most common: oleic acid and its salts, lower alkyl esters associated with alkanes (Cι~C₃) (EP 0267617), oleic acid and/or 2-ethyl-hexanediol (WO 87/03490) and l-dodecylhexahydro-2H-azepin-2-one ("Azone") (EP 0251425), included here as references. Additionally, ethanol, propyleneglycol and other alcohols, long chain fatty acids, etc., have been proposed (R. W. Baker and J. Farrant "Patents in transdermal drug delivery", Drug Delivery Systems 1987 Conference Proceedings). However, none of them have enough suitable characteristics for the manufacture of a transparent diclofenac sodium gel, with a topical, local or systemic effect and a suitable permeation, that do not produce irritation in the user and with a suitable physical stability during its storage and the use by the patient.

SUMMARY OF THE INVENTION

We have found that for diclofenac sodium, one of the best permeation enhancers to be used in a transdermal gel composition having topical, local or systemic effect is oleyl alcohol. However, this compound is insoluble in the aqueous solution that contains the excipients commonly used. When the preparation of a gel containing oleyl alcohol, isopropyl alcohol, propyleneglycol, EDTA and deionised water was intended, an heterogeneous system with two well defined phases was obtained. However, when diclofenac sodium was added to the above described formulation, a clear homogeneous gel was obtained.

The gel composition mentioned above not only has been demonstrated to be, in a completely unexpected way, homogeneous and transparent, without signs of heterogeneity or emulsion, but also has been demonstrated to have special permeation properties.

Oleyl alcohol not only proved to be a particularly suitable permeation enhancer, but also, in an unexpected way, the increase in its concentration did not produce an increase in the amount of diclofenac that permeated through the skin. In this manner, in the permeation experiments studied, it was found that an increase in the amount of oleyl alcohol from 1.5 to 3% do not produce changes in the amount of diclofenac that permeates the skin.

Additionally, we have unexpectedly found that by means of the use of a combination of oleyl alcohol and isopropyl alcohol, in a determined ratio, it is possible to obtain a clear gel for the transdermal administration of diclofenac that is chemically and physically stable, has a local or systemic effect in the user and, at the same time, does not produce irritation in the skin (or reduces such irritation to a low level) .

It is, therefore, one of the objects of the invention, to provide a transparent gel, chemically and physically stable, for the transdermal administration of diclofenac, topical, local or systemic.

It is another object of the invention, to provide a transparent gel, chemically and physically stable, that provides a suitable amount of drug to the skin, for its progressive absorption during a predetermined period of time.

By the invention it is possible to provide a transparent gel, chemically and physically stable for the transdermal administration of diclofenac, that provides a suitable amount of drug during an extended period of time and, at the same time, does not produce irritation in the user.

Also, by the invention it is possible to provide a transparent gel, chemically and physically stable, that provides a permeation of diclofenac higher than that observed in those topical formulations already known in the prior art, that contain the same amount of active ingredient.

The present invention provides a transparent gel composition, for the topical, local or systemic administration of diclofenac through the skin wherein said composition comprises diclofenac sodium in a concentration of 4.2% or higher, preferably 5% or higher, and a mixture of oleyl alcohol and isopropyl alcohol in a ratio in the range 0.02 - 0.125, preferably 0.25 - 0.1, more preferably 0.025 and 0.05. A most preferred ratio is between 0.04 and 0.05.

Although there is no essential upper limit for diclofenac sodium, a suitable maximum is 10%. Most preferably the gel of the invention comprises diclofenac in a concentration of S-

A particularly preferred composition of the invention comprises oleyl alcohol in a percentage of the total weight of the composition in the range 0.75% to 3%, e.g. 1.5%, and isopropyl alcohol in a percentage of the total weight of the composition in the range 15% to 60%, e.g. 30%.

Propyleneglycol is a preferred optional component, preferably in an amount in the range 2 to 20%, e.g. 8%.

One skilled in the art will be able to select other pharmaceutically acceptable excipients for the composition of the invention. For example, the composition may comprise, additionally, any one or more of vehicles, fragrances and thickeners, which are pharmaceutically and cosmetically acceptable . In a particular embodiment, the gel composition of the invention comprises also a chelating agent of bivalent ions such as copper, iron and manganese ions, in particular sodium edetate, which is particularly preferred because it improves the physical stability of the composition while preventing the development of a yellowish colour.

Preferably, the gel composition of the invention comprises, at least one of the following compounds: propyleneglycol, methocel (hydroxypropylmethylcellulose) , methylparaben (p- methylhydrobenzoate) , fragrance, sodium edetate and deionised water.

A particular composition of the invention may comprise, as percentages of the total weight of the composition: diclofenac sodium 5%, isopropanol 30%, propyleneglycol 8%, oleyl alcohol 1.5%, Methocel K-15 1.3%, methylparaben 0.1%, fragrance 0.1%, EDTA 0.01% and deionised water up to 100%.

According to the invention there is also provided a process for preparing a transparent gel composition of the invention as described above, which comprises the steps of dispersing hydroxypropylmethylcellulose in deionised water, mixing diclofenac sodium with the remaining components and pouring the dispersion of hydroxypropylmethylcellulose in water over the obtained mixture.

The gel composition of the invention may be prepared, for example, in the following way: Methocel K-15

(hydroxypropylmethylcellulose) is dispersed in a sufficient amount of deionised water. Isopropanol, oleyl alcohol, propyleneglycol, methylparaben, diclofenac sodium and the fragrance are mixed in a suitable recipient. Then, the dispersion of Methocel in water is poured with constant stirring over the other solution, forming in this way an homogeneous and transparent gel.

Typically the gel is a single phase composition.

All percentages of compositions herein are by weight.

DESCRIPTION OF EXAMPLES AND PREFERRED EMBODIMENTS

Taking into account that the present invention is capable of being performed in many different embodiments, some of the preferred embodiments are described below. However, it must be understood that the present disclosure must be considered as an example of the principles of the invention but it is not directed to limit the invention to the examples specifically illustrated.

Example 1 :

Formulation of a transparent gel of diclofenac sodium according to the present invention.

The gel composition of this example was prepared as follows: 1.3 g of Methocel K-15 (hydroxypropylmethylcellulose) are dispersed in a sufficient amount of deionised water. Isopropanol, oleyl alcohol, propyleneglycol, methylparaben, diclofenac sodium and the fragrance are mixed in a suitable recipient. Then, the dispersion of Methocel in water is poured with constant stirring over the other solution, forming in this way an homogeneous and clear gel.

Example 2 :

The gel composition of this example was prepared in the same way as in Example 1.

Exam le 3 :

Example 4 (comparative) :

The "in vitro" permeation profile through human cadaveric skin of a diclofenac sodium gel without oleyl alcohol against those permeations of commercial gels containing diclofenac diethylamine, "Oxagel®" and "Voltaren®", was compared.

Measurements were performed in triplicate using vertical type cells, with continuous stirring, in a water bath with controlled temperature (34°C) . The cells that were used (also known as diffusion Franz cells) have two chambers: a lower or receptor one in which the receptor solution is placed (phosphate buffer solution at pH 7.4) and an upper or donor one in which the solution to be assayed is placed. In the upper base of the receptor chamber the sample of skin was placed, with the stratum corneum facing upwards, ensuring a perfect contact between the dermis and the receptor solution. A magnetic stirring bar was also placed into the receptor chamber. In the donor chamber 0.5 g of the gel to be studied was placed, ensuring a perfect contact between the semi-solid and the skin.

The receptor chamber was fixed to the donor chamber by means of a paraffin film, while the latter was also sealed with a similar film, to ensure that the assay was performed under occlusive conditions. 2 ml samples of the receptor solution were taken at 2, 4, 6, 8 and 24 hours from the beginning of the assay and the diclofenac content of them was analysed with a suitable HPLC technique. The extraction of the samples was accompanied by replenishment with fresh receptor media.

The obtained values were used to calculate the amount of drug permeated, expressing the results as μg/cm².

The design of the study is briefly described in the following table:

Cells 1 to 3

"Voltaren® "

Diclofenac diethylamine 1.16%

Excipients up to 100%

Cells 4 to 6

"Oxa gel®"

Diclofenac diethylamine 1.16%

Excipients up to 100%

Cells 7 to 9

Diclofenac sodium gel without oleyl aleohol

Diclofenac sodium 5%

Isopropano L 30%

Propyleneglyc ol 8%

Methocel K -15 1.3%

Methylparaben 0.1%

Fragrance 0.1%

Deionised rfater up to 100%

The diclofenac sodium gel without oleyl alcohol was prepared as follows: 1.3 g of Methocel K-15 (hydroxypropylmethylcellulose) were dispersed in 55.5 ml of deionised water. Isopropanol, propyleneglycol, methylparaben, diclofenac sodium and the fragrance were mixed in a suitable recipient. Then, the dispersion of Methocel in water is poured with constant stirring over the other solution, forming in this way an homogeneous and transparent gel.

The results obtained are detailed in the following table:

From the obtained results it can be concluded that a diclofenac sodium gel at 5% that does not contain oleyl alcohol, but contains propyleneglycol at 8%, as permeation enhancer, does not reaches the permeation rates obtained with commercial formulations that contain diclofenac diethylamine 0 at 1.16%. This fact agrees with the higher polarity of the molecule of diclofenac sodium compared with that of diclofenac diethylamine, the less polar molecule being more permeable through the stratum corneum.

5

Example 5 :

The permeation profiles of several gels of diclofenac sodium, containing different concentrations of oleyl alcohol and 0 prepared according to the present invention were compared with the permeation of the commercial gel containing diclofenac sodium "Diclac®".

The measurements were performed as described in the preceding '.5 example, but in this case the samples were extracted at 4, 8 and 24 hours from the beginning of the experiment. The composition of the formulations included in the study is described as follows:

The gels that contain diclofenac sodium within this example were prepared as follows: 1.3 g of Methocel K-15 (hydroxypropylmethylcellulose) are dispersed in 55.5 ml of deionised water. Isopropanol, oleyl alcohol, propyleneglycol, methylparaben, diclofenac sodium and the fragrance are mixed in a suitable recipient. Then, the dispersion of Methocel in water was poured with constant stirring over the other solution, forming in this way an homogeneous and colorless gel. The gel corresponding to formulation 1 was prepared similarly to the corresponding gel of the previous example.

The design of the study is described briefly in the following table :

The obtained results are detailed in the following table:

Surprisingly it was found that contrary to what was expected, there did not exist a linear relationship between the amount of permeation enhancer (oleyl alcohol) and the amount of drug permeated. Thus, the oleyl alcohol concentration that showed the highest permeation was 1.5%. Likewise, in a completely unexpected manner, a marked increase in the permeation of diclofenac was achieved when this parameter was tested in gels containing oleyl alcohol. This increase was notable not only when it was compared with the permeation obtained with a similar formulation, in which said alcohol was absent, but also when it was compared when the commercial product

Diclac®.

Example 6 :

Taking into account the importance of the physical appearance in a gel for its acceptance by patients, this characteristic was studied in several developed compositions. The composition of the formulations used and the physical appearance obtained for each of them is described briefly as follows :

The gels studied here were prepared similarly as in the previous examples.

With the results obtained in the present example it is possible to demonstrate that for obtaining a gel with the desired composition and characteristics, also acceptable from the pharmaceutical point of view, simultaneous presence of oleyl alcohol and diclofenac sodium in the formulation is very advantageous. Thus, for example, it is only possible to obtain a transparent gel containing 1.5% of oleyl alcohol, when the diclofenac sodium is present in an amount higher than 2.5%. Without intending to be restricted to any particular theoretical explanation, from the obtained results it can be concluded that the diclofenac sodium is responsible for the solubilization of oleyl alcohol. Thus, the heterogeneity observed in formulations 5 and 6 could be produced because in them, the oleyl alcohol it is not dissolved.

Example 7 :

Acceptance by volunteers to whom the transparent gel compositions according to the present invention were applied, was evaluated. At the same time, the toxicity of the product at dermal level and the plasmatic levels of diclofenac were evaluated.

0.7 g dose of a diclofenac sodium gel, of formulation 3 or 4, prepared as disclosed in example 5, was applied three times a day during seven days on the forearm of 10 healthy volunteers. A total of 21 applications were made to each volunteer (two applications were made on the first day) . All subjects completed the study and were evaluated periodically for signs of local irritation.

None of the volunteers showed signs of irritation, edema, itching or inflammation in the application area, nor did they inform having suffered side effects. During the studies two blood samples were collected from six of the volunteers. The first blood sample was collected 12 hours after the 8^th application of the gel and the second blood sample was drawn 4 hours after the 9^th application. The blood samples obtained were suitably processed, analysing the plasmatic content of diclofenac through HPLC-ϋV techniques specifically developed.

The obtained results are detailed in the following table:

Application of a diclofenac sodium gel prepared according to formulation 3, from example 5.

Plasmatic levels (ng/ml)

Individual

12 h after 8^th 4 h after 9^th application application

1 5.22 6.13

2 0 5.34

3 3.39 11.19

4 0 4.09

5 0 9.21

6 0 8.27

Mean 1.44 7.37

Application of a diclofenac sodium gel prepared according to formulation 4, from example 5.

The plasmatic levels obtained after the repeated applications of both formulations indicate that the product, even though its high permeation, does not produce plasmatic levels close to the ones achieved through oral administration. This difference gives clinical safety to the preparations.

Claims

1. A transparent gel composition for the topical, local or systemic administration of diclofenac through the skin, which comprises diclofenac sodium in a concentration of 4.2% or higher and a mixture of oleyl alcohol and isopropyl alcohol in a ratio between 0.020 and 0.125.

2. A transparent gel composition according to claim 1 wherein the amount of diclofenac sodium is not more than 10%.

3. A transparent gel composition according to claim 1 or 2, which comprises diclofenac sodium in a concentration of 5% or higher.

4. A transparent gel composition according to any one of claims 1 to 3 wherein said ratio of oleyl alcohol and isopropyl alcohol is between 0.025 and 0.1, preferably between 0.025 and 0.05.

5. A transparent gel composition according to any one of claims 1 or 4, which comprises oleyl alcohol in a concentration in the range 0.75 - 3.0%.

6. A transparent gel composition according to any one of claims 1 to 5, which comprises isopropyl alcohol in a concentration in the range 15 - 60% .

7. A' transparent gel composition according to any one of claims 1 to 6, which comprises propyleneglycol in a concentration in the range 2 - 20%.

8. A transparent gel composition according to any one of claims 1 to 7, which also comprises pharmaceutically acceptable excipients.

9. A transparent gel composition according to claim 8, which comprises hydroxypropylmethylcellulose as an excipient.

10. A transparent gel composition according to any one of claims 1 to 9 which comprises a chelating agent for iron, copper and manganese.

11. A transparent gel composition according to claim 10, wherein the chelating agent of bivalent ions is sodium edetate .

12. A transparent gel composition according to claim 11, wherein the sodium edetate prevents the composition from acquiring a yellowish colour.

13. A transparent gel composition according to claim 1, which has the following composition:

14. A process for the preparation of a transparent gel composition according to any one of claims 1 to 13, which comprises the steps of dispersing hydroxypropylmethylcellulose in deionised water, mixing diclofenac sodium with the remaining components and pouring the dispersion of hydroxypropylmethylcellulose in water over the obtained mixture .