MXPA98002828A - Farmaceut formulation - Google Patents

Abstract

The present invention relates to a new pharmaceutical formulation for the topical application of nonsteroidal anti-inflammatory drugs (NSAIDs), comprising: (a) a therapeutically effective amount of a drug, (b) a sodium phosphate buffer, and , optionally, (c) an alcohol solvent

Description

"PHARMACEUTICAL FORMULATION" Field of Invention The present invention relates to a new pharmaceutical formulation for the topical application of drugs, in particular, of non-steroidal anti-inflammatory drugs (NSAIDs).

Background of the Invention In view of the adverse reactions of drugs associated with oral formulations, NSAIDs are increasingly administered by topical route. A prerequisite for success in the topical medication of NSAIDs is that the drug is sufficiently permeable through the skin into the tissues such as the subcutis, fascia, tendons, ligaments and muscles for the treatment of alterations. degenerative and post-traumatic inflammatory structures of soft tissues. Hydroalcoholic formulations, for example, ethanol / water and propylene glycol / ethanol / water are formulations commonly used for the topical application of NSAIDs. In accordance with the present invention it has been discovered that REF: 27132 By the addition of a sodium phosphate buffer to said formulations the permeation of the NSAIDs can be significantly improved.

Description of the invention.

Accordingly, the invention relates to a formulation for the topical application of drugs, particularly non-steroidal anti-inflammatory drugs (NSAIDs) which formulation comprises: (a) a therapeutically effective amount of a drug; (b) a sodium phosphate buffer; and optionally, (c) an alcohol solvent.

The formulations according to the present invention may be presented in any conventional form of application. They are examples of such forms of application, solutions, foams, creams, ointments, lotions and gels.

The drug contained in the formulation according to the invention can be any drug that is conventionally applied topically. They are drugs of primary interest for use in the present invention, NSAIDs such as naproxen, ibuprofen, indomethacin, diclofenac, piroxicam or etofenamat and the pharmaceutically acceptable salts thereof. A preferred NSAID for the purpose of the invention is naproxen. Any salt that is conventionally employed in pharmaceutical preparations for NSAIDs can be used. Examples of such salts are alkali metal salts such as sodium salts and potassium salts, and substituted ammonium salts such as salts with alkylamines and hydroxyalkylamines, for example, diethylamine and triethanolamine. The appropriate molarity of the sodium phosphate buffer is in the range from about 10 to 300 mM, preferably about 100 to about 200 mM. The pH of the buffer solutions is approximately between 5 and 7.5, more preferably from 6.0 to 7.5. Most preferred is a pH of 6.0. The alcohol solvent may be any solvent conventionally employed in topical formulations. The preferred alcohol solvents are ethanol, isopropanol, propylene glycol and mixtures thereof. Another example of an alcohol solvent is glycerin. Preferred alcoholic solvents are mixtures of ethanol and propylene glycol in a proportion of 3: 1 parts by weight.

If a gel formulation is desired, any gel-forming agent commonly used in pharmaceutical gel formulations can be employed. Examples of gel-forming agents are cellulose derivatives such as methyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose; vinyl polymers such as polyvinyl alcohols, polyvinyl pyrrolidones; and polyacrylic derivatives such as Carbopol. Other gel-forming agents which can be used for the compositions according to the invention are pectins, gums, such as gum arabic and tragacanth, alginates, carrageenans, agar and gelatin. The preferred gel-forming agent employed in the present invention is hydroxypropylmethyl cellulose (HPMC). In addition, the gel formulation of this invention may also contain auary agents commonly employed in such formulations such as preservatives, antioxidants, stabilizers, colorants and perfumes.

The amount of active ingredient present in the formulations of the present invention is generally the same as in the corresponding conventional formulations. If the drug, ie, the active substance, is an NSAID, its amount may vary, for example, from about 0.1 to about 10 g of NSAID per 100 g of finished formulation, preferably 0.5-2.5. g, and more preferably about 1 g per 100 g of finished formulation. The amount of sodium phosphate buffer may vary from about 30 to about 90-99 g, preferably from about 30 to about 70 g of a 100-200 mM solution per 100 g of finished formulation. The amount of the most suitable alcohol solvent is from about 5 to about 70 g per 100 g of finished formulation. In a preferred aspect of the invention, the alcohol solvent comprises about 20 to about 40 g of ethanol and about 5 to about 30 g of propylene glycol. In gel formulations the amount of gel-forming agent sufficient to obtain a gel formulation having a viscosity suitable for application to the skin depends on the particular gel-forming agent or agents employed and the desired viscosity of the finished formulation. of gel, and can be determined by the expert in pharmaceutical formulation according to the individual requirements.

The formulations according to the present invention can be prepared in a conventional manner. For example, the drug is dissolved, for example, an NSAID in the aqueous solution of the buffer and optionally the alcohol co-solvents. The solution obtained can then be gelled by addition of the gelling agent, for example, hydroxyethylcellulose or hydroxypropylmethyl cellulose.

The following examples illustrate the invention: Example 1.

A gel was prepared from the following constituents: Constituent (grams) Naproxen sodium 1, 1 Ethanol 30.0 Propylene glycol 10.0 Aqueous phosphate buffer of 50.0 sodium pH 6.0 200 mM Hydroxyethyl cellulose 1.6 Water q.s. for 100.0 Example 2 A gel was prepared from the following constituents: Constituent (grams) Naproxen sodium 1, 1 Ethanol 30.0 Propylene glycol 10.0 Aqueous buffer of 50.0 sodium phosphate pH 6.0 100 mM Hydroxypropylmethyl cellulose 2.5 Water q.s. for 100.0 Example 3 A gel was prepared from the following constituents: Constituent (grams) Naproxen (free acid) 1.0 Triethanolamine 0.65 Ethanol 30.0 Propylene glycol 10.0 Aqueous phosphate buffer 50.0 sodium pH 6.0 200 mM Hydroxyethyl cellulose 1.6 Water q.s. for 100.0 Example 4 A gel was prepared from the following constituents: Constituent (grams) Naproxen sodium 2, 74 Ethanol 30.0 Propylene glycol 10.0 Aqueous phosphate buffer of 50.0 sodium pH 6.0 200 mM Hydroxyethyl cellulose 1.6 Water q.s. for 100.0 Example 5.

A gel was prepared from the following constituents: Constituent (grams) Naproxen sodium 5, 5 Ethanol 30.0 Propylene glycol 10.0 Aqueous phosphate buffer of 50.0 sodium pH 6.0 200 mM Hydroxyethyl cellulose 1.6 Water q.s. for 100.0 Example t A gel was prepared from the following constituents: Constituent (grams) Naproxen sodium 1.1 Ethanol 30.0 Propylene glycol 10.0 Aqueous phosphate buffer 50.0 sodium pH 6.0 0 100 mM Hydroxyethyl cellulose 1.6 Water q.s. for 100.0 Example 7 A gel was prepared from the following constituents: Constituent (grams) Naproxen sodium 1.1 Aqueous phosphate buffer of 50.0 sodium pH 7.25 100 mM Hydroxyethyl cellulose 1.6 Water q.s. for 100.0 Example 8 Studies of skin permeation: The naproxen skin permeation of the formulations according to the invention (Example 1) was measured from the corresponding unbuffered formulation (formulation B) and from a prior art formulation (NaprosynGEL ™, formulation A) . Formulations A and B were prepared with the composition indicated below: Formulation AB (grams) Naproxen (free 10.0 acid) Naproxen sodium 1.1 Triethanolamine 13.0 Ethanol 30.0 30.0 Propylene glycol - 10.0 Hydroxyethyl 1,6 cellulose Carbomer 940 2 0.1 sodium metabisulfite Perfume Roses 0.03 Water cs for 100.0 100.0 Samples of abdominal skins from human cadavers (0.38 mm) were dermatomized and frozen at -80 ° C. On the day of the experiment the skin samples were thawed and introduced into Franz type diffusion cells, with a cross-sectional diffunal area of 1 cm2 and a 5 ml receptor chamber volume. The receiving compartments, equipped with magnetic stirring bars, were filled with phosphate buffered saline solution of 1 Mm, pH 7.4. The diffusion cells were then passed to heating boxes thermostated at 32 ° C. After a balancing period of 3-4 hours, 5 mg / cm2 of the test formulations were applied to the epidermal surfaces using micropipettes. After 45 hours of incubation under non-occlusive conditions at 32 ° C, the receptor solutions were removed and the concentrations of naproxen were measured by HPLC. The results are indicated in Figure 1, where the in-permeation of naproxen is shown from NaproxynGEL (A) gels, propylene glycol / water ethanol (B) and propylene glycol / ethanol / sodium phosphate buffer (example 1) through the skin of a human corpse. Each column represents the geometric mean of seven experiments performed with the skin of seven different donors.

*** = P < 0.005, NS = not significant; compared to NaprosynGEL in the Student t-test of peer values.

It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Having described the invention as above, the content of the following is claimed as property.

Claims (9)

1. A pharmaceutical formulation for the topical application of drugs, which formulation is characterized in that it comprises: (a) a therapeutically effective amount of a drug; (b) sodium phosphate buffer; and optionally, (c) an alcohol solvent.

2. The formulation as in claim 1, characterized in that the drug is a non-spheroidal anti-inflammatory drug (NSAID).

3. The formulation as in claim 2, characterized in that the NSAID is naproxen, ibuprofen, indomethacin, diclofenac, piroxicam or etofenamat or a pharmaceutically acceptable salt thereof.

4. The formulation as in any one of claims 1 to 3, characterized in that the sodium phosphate buffer is a 10 to 300 mM aqueous sodium phosphate buffer of pH 5 to 7.5.

5. The formulation as in any one of claims 1-4, wherein there is an alcohol solvent comprising ethanol, isopropanol and propylene glycol or mixtures thereof.

6. A formulation of a gel as in any one of claims 1-5, characterized in that it comprises per 100 g of formulation: (a) about 0.1 to about 10 g of NSAID (b) about 30 to about 70 g of 100-200 mM sodium phosphate buffer of pH 6-7.5; (cl) about 20 to about 40 g of ethanol and / or isopropanol; (c2) about 5 to about 30 g of propylene glycol; Y (d) at least one gel-forming agent in an amount sufficient to obtain a gel formulation having a suitable viscosity to be applied to the skin.

7. The formulation of a gel as in claim 6, characterized in that the gel-forming agent is hydroxypropylmethyl cellulose.

8. The formulation as in any one of claims 1-7, characterized in that the drug is naproxen sodium.

9. The formulation of claim 8, characterized in that the drug is about 1% naproxen sodium.