JPH0261442B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION This invention relates to compositions for topical therapy to the skin, and more particularly to pharmaceutical topical formulations.

In particular, it is well known that therapeutic agents can be applied to the skin, for example as ointments, creams and lotions.
Various skin affiictions can be used as vehicles through which therapeutic agents can be administered to the skin.
They are sensitive to composition in different ways. For these injuries that cause the skin to become dry and flaky,
The use of ointments is generally preferred. Ointments usually contain more oil (fatty ingredients) than water. On the other hand, there are skin lesions where it is not advisable to wrap the skin to avoid drying, and in these cases the use of creams containing more water than oil is preferred. Ointments have the disadvantage of sticking to objects they come into contact with and causing oil stains, which are not easily removed by normal washing of the skin and clothing that come into contact with the ointment. Lotions are generally non-viscous, so the therapeutic agent contained therein is in contact with the skin for only a relatively short period of time as the lotion runs off.

In order to obtain a stable medium for water-containing ointments and creams, emulsifiers (surfactants) are used in their preparation. Lipophilic emulsifiers (“dissolve” water in oil)
There are hydrophilic emulsifiers (which "dissolve" oil in water, ie, O/W emulsifiers), or hydrophilic emulsifiers (which "dissolve" oil in water, ie, O/W emulsifiers). In the case of ointments (more oil than water), W/O emulsifiers are usually used; these ointments consist of a continuous oil phase in which small water particles are present. In the case of creams (more water than oil), O/W emulsifiers are used; this cream consists of a continuous aqueous phase, in which small oil particles are present. To identify whether a formulation is an ointment or a cream, a colored compound that dissolves in either the oil phase or the aqueous phase can be used and is identified by microscopy.

As already mentioned cream (more water than oil)
Oil-in-water (O/W) type emulsifiers are used in the production of. It has now been found that stable compositions in the form of "oil-in-water fatty creams" containing more fatty compounds than water can be obtained using hydrophilic O/W nonionic emulsifiers (i.e. surfactants). This was completely unexpected.

Accordingly, the present invention comprises a fatty base, water, at least 1
A stable "oil-in-water fatty cream" composition for topical treatment of the body, comprising a hydrophilic non-ionic surfactant and a topically active therapeutic agent, the composition comprising 50-80% by weight (preferably contains 60-70% fatty substance(s) and 1.5-5% by weight surfactant.

“Oil-in-water fatty cream” of the present invention (hereinafter referred to as
Fatty creams) can be manufactured using conventional methods of ointment and cream manufacturing. Microscopic examination of the product indicates whether the mixing intensity was sufficient to produce a uniform oil-in-water (O/W) emulsion. Insufficient mixing can result in a picture of a composite emulsion under the microscope, with the continuous phase being an oily component in some parts of the emulsion. When applied to the skin, this fatty cream has a skin-enveloping effect due to its high oil content. The skin becomes moist and therefore more permeable by the therapeutic agents used thereon. Moreover, this fatty cream, in contrast to ointments, can be easily removed from the skin and materials that come into contact with it.

The fatty substances incorporated in this fatty cream of the invention are those commonly used in the manufacture of ointments and creams. Preferably a mixture of fatty compounds (solid, semi-solid and/or liquid at ambient temperature) is used for the production of this fatty cream. These fatty compounds include, for example, waxes (e.g. white petrolatum), liquid paraffin, fatty alcohols and esters (e.g. cetylstearyl alcohol, myristyl alcohol and glycerin monostearate), vegetable oils (e.g. cottonseed oil, coconut oil, soybean oil,
or peanut oil), mineral oil or liquid silicone.
Preferably a combination of cetylstearyl alcohol, liquid paraffin and white petrolatum is used.

The amount of hydrophilic nonionic surfactant (liquid or solid) used in the preparation of the fatty cream of the invention is suitably between 1.5 and 3.5% (advantageously 3%) of the weight of the final composition. . The surfactant (i.e. emulsifier) preferably has a high HLB number (Hydrophilic- Lipophile−
balance). Advantageously that
HLB number must be 14 or more. The surfactant is preferably setomarogol 1000 (i.e.
Polyethylene glycol (1000) monocetyl ether). Other surfactants that may be used are Polysorbate 60 (i.e. polyoxyethylene 20 sorbitan monostearate)
and polysorbate 80 or Tween 80 (ie polyoxyethylene (20) sorbitan monooleate). Preferably only one surfactant is used.

The amount of water (preferably deionized water) used in the preparation of the fatty cream of the invention is based on the weight of the final composition.
It can range from 20 to 35%. Approximately 30% water is advantageously used.

The locally active therapeutic agent incorporated into the fatty cream of the present invention may be a steroid (eg, an anti-inflammatory steroid), an antibiotic, or a chemotherapeutic agent, or a combination of such therapeutically useful agents. The therapeutic agents include, for example, hydrocortisone-17α-butyrate, hydrocortisone, triamcinolone acetonide, salicylic acid and its derivatives, tar products,
These are sulfur compounds, iodine compounds, nicotinic acid and its derivatives, hexachlorophene or retinoic acid. The amount of therapeutic agent that may be soluble in the aqueous or oily phase of the fatty cream will be that amount appropriate for the intended application.

If the therapeutic agent (e.g. hydrocortisone-17α-butyrate) is soluble in the aqueous phase of the fatty cream,
Since the therapeutic agent is dissolved in a smaller amount of water than in conventional creams and ointments, leading to a higher concentration of the therapeutic agent, better activity can be obtained than in these creams and ointments.

It may be useful to include a buffering agent in the fatty cream of the present invention to maintain the desired PH value.
This buffer may be, for example, a combination of (i) citric acid and sodium citrate, (ii) phosphoric acid and sodium phosphate, or (iii) lactic acid and sodium lactate, as appropriate to the desired PH. The therapeutic agent is hydrocortisone-17α-
In the case of butyrate, a slightly acidic environment (e.g. PH3.5~
4.5), for which the combination of citric acid and sodium citrate is particularly useful.

The fatty creams of the invention may also contain preservatives, as in the common practice of ointments and creams, for example to prevent bacterial attack. Suitable preservatives are methyl hydroxybenzoate, chlorocresol, sorbic acid and benzoic acid.

As already mentioned, the fatty cream of the invention can be manufactured by conventional methods. A preferred method is to mix the "fatty" ingredients (e.g. cetylstearyl alcohol, liquid paraffin and white petrolatum) with a hydrophilic non-ionic surfactant (preferably cetomacrogol 1000) and heat the mixture at e.g. 70-80°C. It includes heating. Separately in a suitable ointment mixer mix water (preferably deionized water), buffer and preservative until a solution is obtained (e.g.
Heat (at 70-80°C). A small portion of the resulting solution is separated, cooled to ambient temperature, and the therapeutic agent is then added thereto. Add the liquid fatty composition to a large portion of its aqueous solution under elevated temperature (e.g. 70-80 °C) and add the therapeutic agent after vigorous stirring under reduced pressure (to avoid air bubbles in the final fatty cream). An aqueous solution or suspension containing the mixture is added thereto under normal pressure. The mass is vigorously stirred at about ambient temperature for a suitable period of time, again under reduced pressure, to obtain a fatty cream.

The temperature of the final mixing of the components of the fatty cream and the agitation involved are determined by the type of emulsion obtained (oil-in-water and/or water-in-oil).
affect. It is preferably carried out at 20-25°C with vigorous stirring.

The fatty cream of the present invention thus obtained is preferably an "oil" having an average diameter of 1 to 2 μm (length and height of 5 μm).
Consists of particles. Due to the high fat content, it is usually hardly found in the aqueous phase. Presumably, water is deposited on the particle surface as a thin film, still forming a continuous phase.

The fatty smooth creams of the invention can be very stable under normal conditions, especially if they are emulsions containing mainly oil particles of very small average diameter, for example 1 to 2 μm.

The present invention also encompasses fatty creams that do not incorporate therein one or more topically active therapeutic agents as described above, and methods of preparing such topical cream bases.

The following examples illustrate the preparation of fatty creams according to the invention.

Example 1 50Kg of fatty cream was prepared as follows:
-3000g cetylstearyl alcohol, 1500g
of Setomacrogol, 9000 g of liquid paraffin and 21000 g of white petrolatum were mixed together;
Heated to 70-80°C.

A suitable ointment mixer (e.g. Heagen and Rina
u, 50Kg Unimix manufactured in (Bremen, West Germany),
In it, 60g sodium citrate, 90g citric acid and 100g methyl hydroxybenzoate.
Added to 15500g deionized water. The mixture was heated to 70-80°C with stirring and kept at this temperature until the compound dissolved. 2000 g of the resulting solution was removed and cooled to room temperature.

The prepared liquid fatty composition was added to the remaining solution at 70-80°C. After vigorous mixing under reduced pressure (50 mmHg), the agglomerate was gradually cooled to 20-25°C.

50 g of hydrocortisone-17α-butyrate was evenly suspended in the aqueous solution of this separated portion (e.g. Janke and Kunkel, West Germany).
in an Ultra-Turral mixer). After breaking the vacuum in the ointment mixer using perair, the suspension containing hydrocortisone-17α-butyrate was added to the cream. Seal the mixer
The cream was homogenized after vigorously mixing the contents under reduced pressure (50 mmHg) for at least half an hour. After breaking the vacuum its fatty cream (50
Kg) into a container that can be filled into tubes or jars.

When examined under a microscope, this fatty cream has a
It was composed of oil particles with an average diameter of ~2 μm, with larger ones up to 5 μm.

Example 2 The procedure of Example 1 was repeated to obtain a fatty cream, but with 500 g of hydrocortisone instead of 50 g of hydrocortisone-17α-butyrate.
15050g of deionized water was used instead of 15500g.

Example 3 The procedure of Example 1 was repeated to obtain a fatty cream, but using 50 g of triamcinolone acetonide instead of 50 g of hydrocortisone-17α-butyrate.

Example 4 The procedure of Example 1 was repeated, but the hydrocortisone-17α-butyrate (ie, the therapeutic agent) was omitted; as a result, the step of separating 2000 g of the aqueous solution produced was not performed.

A fatty cream base was obtained which can be used as a medicinal or therapeutic aid.

Examples 5-8 The operations of Examples 1-4 were repeated, but the cetylstearyl alcohol was replaced with glyceryl monostearate.

Examples 9-12 The operations of Examples 1-4 were repeated, but cetomacrogol 1000 was replaced with polysorbate 80.

Examples 13-16 The operations of Examples 1-4 were repeated, but the liquid paraffin was replaced with a vegetable oil selected from cottonseed oil, refined coconut oil, and soybean oil.

Examples 17-20 The operations of Examples 1-4 were repeated, but some or all of the white petrolatum was replaced by a corresponding amount of hydrogenated peanut oil.

Examples 21-24 The operations of Examples 1-4 were repeated, but citric acid and sodium citrate were replaced with other buffer systems, namely phosphoric acid and sodium phosphate, the ratio of which was adjusted to give the desired PH value. It has been corrected.

Examples 25-28 The procedure of Examples 1-4 was repeated but without the addition of buffering agents (i.e. citric acid and sodium citrate).

Examples 29-32 The operations of Examples 1-4 were repeated, but the methyl hydroxybutyrate was replaced with another preservative selected from chlorocresol, sorbic acid and benzoic acid.

All products of Examples 5-32 were fatty creams similar to those obtained in Example 1.

Claims (1)

[Scope of Claims] 1. A composition in the form of an oil-in-water fatty cream for local treatment of the body, comprising a fatty base, water, and at least one hydrophilic nonionic surfactant, the composition comprising: fatty substance(s) containing 50-80% by weight
and 1.5 to 5% by weight of a surfactant. 2. The composition of claim 1 containing a locally active therapeutic agent. 3. A composition according to claim 1 or 2, wherein the amount of fatty substance(s) is between 60 and 70% of the weight of the composition. 4. Claims 1, 2, or 3, wherein the fatty substances included in the composition are cetylstearyl alcohol, liquid paraffin, and white petrolatum.
The composition described in Section. 5. The composition according to any one of claims 1 to 4, wherein the amount of surfactant is 1.5 to 3.5% of the weight of the composition. 6. The composition according to any one of claims 1 to 5, wherein the hydrophilic nonionic surfactant is Cetomacrogol 1000. 7. A composition according to any one of claims 1 to 6, wherein the amount of water present is between 20 and 35% of the weight of the composition. 8 Claim 7 in which the amount of water is 30% by weight
The composition described in Section. 9. The composition according to any one of claims 2 to 8, which contains a steroid as a therapeutic agent. 10 The steroid is hydrocortisone-17α-
10. The composition of claim 9 which is a butyrate. 11. The composition according to any one of claims 1 to 10, which contains a buffer to maintain a desired pH value in the composition. 12. The composition of claim 11, wherein the buffering agent is a combination of citric acid and sodium citrate. 13 Claims 1 to 1 containing preservatives
The composition according to any one of item 2.