HU207446B - Method for producing medicinal preparation of local use - Google Patents

Abstract

Ointment,. hydrogel or stick to alleviate pain caused by calcification due to rheumatic complaints, degenerative and post-traumatic deposition contains: EDTA sodium salt, camphor menthol, opt. anti-inflammation cpd. pref. ethylene-glycol-salicylate, anaesthetic pref. procaine, antioxidant, glutathione, and vehicle pref. hydroxy-methyl-cellulose, glycerol, preservatives

Description

The present invention relates to a process for the preparation of new topical pharmaceutical compositions (such as ointments, gels and sticks). The compositions of the present invention have primarily anti-inflammatory, analgesic and anti-limescale activity, and are particularly useful in the therapeutic treatment of inflammatory rheumatoid and denegerative joint diseases and of post-traumatic lime deposits.

For the local symptomatic treatment of rheumatic pain, abrasives (such as ointments, balms and gels) containing camphor and / or menthol have long been used. These formulations exhibit local analgesic activity and exhibit mild smooth muscle antispasmodic and anti-inflammatory activity.

The sodium salt of ethylenediaminetetraacetic acid has been used in medicine to date for the treatment of acute metal poisoning and rheumatic diseases in the form of oral formulations (oral compositions or injections) (Issekutz: Pharmaceutical Order 480 (Medicina Publisher, 1978)). However, these internally administered preparations bind trace elements in the body and are therefore not recommended for long-term administration.

The sodium salt of ethylenediaminetetraacetic acid has not yet been used as an active ingredient in topical formulations for topical administration. This is probably due to the fact that we also find that the sodium salt of ethylenediaminetetraacetic acid is not or only very slightly absorbed through the skin.

Surprisingly, the addition of an alkaline metal salt of ethylenediaminetetraacetic acid (preferably the sodium salt of ethylenediaminetetraacetic acid) to the topical formulations containing camphor and menthol has synergistically enhanced the anti-inflammatory effect of the composition. It has also been found that these compositions effectively eliminate calcareous deposits during topical treatment, thereby greatly reducing or completely eliminating nerve pain caused by mechanical stimuli in calcification disorders. Thus, in the treatment of rheumatic and degenerative joint pain and inflammation associated with lime deposits, topical formulations containing camphor, menthol, and an alkaline metal salt of ethylenediaminetetraacetic acid produce not only symptomatic analgesic or anti-inflammatory effects, but are also useful in treating the disease.

It has also been found that the addition of ethylene glycol monosalicylate to topical formulations containing camphor, menthol and an alkali metal salt of ethylenediaminetetraacetic acid further synergistically enhances the anti-inflammatory effect of the formulation.

The present invention therefore relates to a process for the preparation of a topical pharmaceutical composition having an anti-inflammatory, analgesic and anti-limescale effect, comprising 0.5-1% by weight of camphor, 0.5-1% by weight of menthol, 1.5% by weight of the composition. -5.5% by weight of alkali metal ethylenediaminetetraacetic acid and optionally 2.5-6% by weight of ethylene glycol monosalicylate in admixture with excipients, diluents and / or other excipients used in the preparation of topical pharmaceutical compositions, in known manner.

The pharmaceutical compositions of the present invention may, if desired, be supplemented with known adjuvants, such as anesthetics (such as procaine).

Ointments and gels may be prepared using conventional known ointment and gel bases such as methyl, ethyl, hydroxymethyl or hydroxyethyl cellulose, glycerol and water. Ointments and gel bases may optionally be supplemented with customary pharmaceutical auxiliaries, such as preservatives, antioxidants (such as glutathione), colorants and / or perfumes.

Generally, an aqueous solution containing an ethylenediamine tetraacetic acid alkaline metal salt and optionally ethylene glycol monosalicylate and / or an auxiliary agent is added to a pre-formulated base material (e.g., an ointment or gel base), and then, after homogenizing the mixture, a mixture of menthol liquefied by rubbing.

The anti-inflammatory activity and the synergistic enhancement achieved by the compositions of the present invention were demonstrated by:

Male mice from the CFLP strain, SPF hygiene category (LATI, Gödöllő) weighing 22-25 g were used for the experiments. Each study was performed on groups of 20-20 mice. The animals were housed in Type I macro-ion boxes, in groups of five, on hardwood shavings. The temperature of the animal room was 20 ± 3 ° C and the relative humidity was 5070%. Artificial alternative illumination was used. During the observation and study period, the animals were allowed to consume any amount of standard pressed laboratory rodent nutrition and tap water LATI-Altromin. The animals were observed for 1 week prior to the start of the study; healthy animals (free from abnormal clinical symptoms) were used for the studies.

To induce inflammation, both ears of the animals were brushed with 10-10 μΐ 2% w / v absolute alcohol croton oil solution. The right ear of the animals was immediately smeared with 10 mg of ointment to be tested; the untreated (left) ear served as a control. Five hours after treatment with croton oil, the animals were sacrificed under ether narcosis, both ears of the animals were slaughtered, their weights were weighted, and the percent inhibition was calculated from the weight differences.

The following ointment samples were tested:

"A": Known ointment base containing methyl cellulose, glycerol and deionized water;

"B": the above ointment base containing 0.9% camphor and 0.9% menthol;

"C" is the above ointment base containing 0.9% camphor, 0.9% menthol and 5% ethylene glycol monosalicylate;

"D": The above ointment base containing 2.5% by weight of sodium salt of ethylenediaminetetraacetic acid;

"E": 0.9% by weight of camphor, 0.9% by weight of menthol and

HU 207 446 Β

The above ointment base containing 2.5% by weight of sodium salt of ethylenediaminetetraacetic acid;

"F": 0.9% by weight camphor, 0.9% menthol,

The above ointment base contains 2.5% by weight of sodium salt of ethylenediaminetetraacetic acid and 5% by weight of ethylene glycol monosalicylate.

The results are reported in Table I below.

Table I

Pattern sign Average weight of mouse ears Inhibition% control Handled "THE" 49.3 ± 10.3 41.2 ± 6.5 16.3 "B" 50.2 ± 7.0 39.2 ± 6.7 21.8 "C" 41.5 + 9.0 33.5 + 6.6 27.1 "D" 50.9 + 10.2 41.9 ± 9.1 17.7 "E" 46.4 ± 9.0 33.7 ± 5.5 27.6 "F" 54.8 + 10.6 37.5 + 6.6 31.7

From the data in Table I, it can be concluded that the sodium salt of ethylenediaminetetraacetic acid (which has an anti-inflammatory effect only slightly higher than that of the ointment base, which is considered essentially ineffective) synergistically enhances both camphor and menthol and camphor, menthol and preparation with anti-inflammatory effect.

The reduction of calcareous deposits was studied in three volunteers. During the study period, a total of 200 g of an ointment containing 4% by weight of ethylenediaminetetraacetic acid sodium salt, 0.9% by weight camphor and 0.9% by weight menthol was applied to the cervical spine of patients, and the degree of calcification of the vertebrae was monitored. In all three subjects, the D vertebrae formed reduced in size and rounded after treatment; the change was significant in all three cases.

The invention is further illustrated by the following non-limiting Examples.

In the examples, the term EDTA refers to the sodium salt of ethylenediaminetetraacetic acid. The chemical composition of the components under the trade name or trademark in the examples is as follows:

Cremophor EL: polyoxyethylated castor oil (manufactured by:

BASF, Ludwigshafen, Federal Republic of Germany)

Carbopol934: Carboxy Polymethylene (manufactured by BF Goodrich, UK)

Tween 60: Polyoxyethylene sorbitan monolaurate (manufactured by ICI, United Kingdom)

Example 1

An ointment having the following composition is prepared:

EDTA 2.5g Camphor 0.9 g Menthol 0.9 g Procaine HCl 0.2 g

Methyl cellulose 4.0 g

Glycerin 8.0 g

Deionized water gives 100.0 g

The methylcellulose is swollen in a portion of deionized water at room temperature for 2 hours, heated in a hot water bath to 80 ° C, stirred and then allowed to cool to body temperature. The mixture is mixed with glycerol and adjusted to 80 g with deionized water.

The EDTA and procaine HCl were dissolved in 17 g of water with gentle heating and the solution was adjusted to 20 g with deionized water. The resulting solution is mixed with 60 g of the ointment base prepared above. Then a mixture of camphor and menthol liquefied by rubbing is added to the mixture, and the rest of the ointment base is then mixed.

Example 2

An ointment having the following composition was prepared according to the procedure described in Example 1:

EDTA 2.5 g

Camphor 0.9 g

Mentol 0.9 g

Procaine HCl 0.2 g

Hydroxyethyl cellulose 4.0 g

Glycerin 8.0 g

Deionized water gives 100.0 g

Example 3

An ointment having the following composition is prepared according to the procedure described in Example 1:

EDTA 2.5 g

Ethylene glycol monosalicylate 5.0 g

Glutathione 1.0 g

Camphor 0.9 g

Mentol 0.9 g

Procaine HCl 0.2 g

Methyl cellulose 4.0 g

Xanthan gum 0.5 g

Cremophor EL emulsifier 8.0 g

Deionized water adl00.0g

Example 4

An ointment having the following composition was prepared according to the procedure described in Example 1:

EDTA 2.5 g

Camphor 0.9 g

Mentol 0.9 g

Procaine HCl 0.2 g

Methyl cellulose 4.0 g

Glycerin 8.0 g

Xanthan gum 0.5 g

Cremophor EL 5.0 g

Distilled water gives 100.0 g

Example 5

An ointment having the following composition was prepared according to the procedure described in Example 1:

EDTA 2.5 g

Camphor 0.9 g

HU 207 446 Β

Menthol 0.9 g Procaine HCl 0.2 g Ethylene glycol monoszalicilát 5.0 g Sorboxethene stearate 4.0 g Paraffin 2.0 g Cetostearyl alcohol 6.0 g vaseline 10.0 g Distilled water ad 100.0g

Carbopol 934 1.0 g Glycerol 8.0 g Trieatanol amine 1.5 g EDTA 2.5 g Camphor 0.9 g Menthol 0.9 g xanthan gum 0.5 g Distilled water ad 100.0 g

Example 6

By following the procedure described in Example 1,

hand gel: EDTA 2.5 g Procaine HCl 0.2 g Camphor 0.9 g Menthol 0.9 g Methyl cellulose 4.0 g xanthan gum 0.5 g Cremophor EL 5.0 g Glycerol 8.0 g Distilled water ad 100.0 g

Example 7

The procedure of Example 1 is followed except that the ingredients of the ointment base are

thaw at 70 ° C and read the Add EDTA and procaine HCl. with aqueous solution, then separate ethylene glycol monosalicic acid and finally the camphor and the Menthol rubbing drain cured mixture. The following composition of ointment is stated- they come up with: EDTA 2.5 g Procaine HCl 0.2 g Ethylene glycol monoszalicilát 5.0 g Camphor 0.9 g Menthol 0.9 g Tween 60 4.0 g paraffin oil 2.0 g Cetostearyl alcohol 6.0 g vaseline 10.0 g Distilled water ad 100.0 g

Example 8 By following the procedure described in Example 1, hand gel: Carbopol 934 2.0 g Glycerol 8.0 g Triethanolamine 2.0 g EDTA 5.0 g Camphor 0.9 g Menthol 0.9 g Distilled water ad 100.0g

Example 9

The gel of the following composition was prepared according to the procedure described in Example 1;

Example 10

By following the procedure described in Example 1,

hand gel: Carbopol 934 1.5 g 1,2-Propylene glycol 8.0 g Triethanolamine 2.0 g EDTA 2.5 g Camphor 0.9 g Menthol 0.9 g Distilled water ad 100.0 g

II. example

By the procedure described in Examples 1,

hand gel: Carbopol 934 2.0 g 1,2-Propylene glycol 8.0 g Triethanolamine 1.5 g EDTA 2.5 g Camphor 0.9 g Menthol 0.9 g Distilled water 100.0 g

Example 12

Using the procedure described in Example 7,

ointment: EDTA 2.5 g Sorboxethene stearate 4.0 g Paraffin 4.0 g Stearate, cetyl alcohol 12.0 g White Vaseline 20.0 g Camphor 0.9 g Menthol 0.9 g Distilled water ad 100.0 g

Example 13 By the procedure described in Example 7, ointment: EDTA 2.5 g Cremophor EL 4.0 g Paraffin 4.0 g Cetostearyl alcohol 12.0 g White Vaseline 20.0 g Ethylene glycol monoszalicilát 5.0 g Camphor 0.9 g Menthol Q, 9g Distilled water ad 100.0 g

Claims (1)

PATIENT PERSONALITY Process for the preparation of topical medicaments, comprising from 0.5 to 1% by weight of camphor, from 0.5 to 1% by weight of menthol, from 1.5 to 5.5% by weight of ethylenediamine tetraethetic acid alkali metal, and optionally 2.5-6% by weight of ethylene glycol monosalicylate is mixed with the carrier, diluent and / or other excipients used in the preparation of topical pharmaceutical formulations to form a pharmaceutical composition in a known manner.