The extract of the pericarp zanthoxylum bungeanum, pharmaceutical and cosmetic composition

 

The invention relates to medicine and concerns extract of Zanthoxylum bungeanum, obtained by extraction of its pericarp supercritical CO₂analgesic activity of the extract used in the treatment of itching. The invention also are pharmaceutical and cosmetic compositions based on the extract. 3 S. and 2 C.p. f-crystals, 2 tab., 1 Il.

The present invention relates to a new extract obtained by extraction of the pericarp Zanthoxylum bungeanum carbon dioxide and pharmaceutical and cosmetic compositions containing it. This extract has anti-inflammatory and analgesic effect and can be used in the treatment of itching.

The pericarp Zanthoxylum bungeanum traditionally used in China as a food spice. In addition, in Chinese and Indian traditional medicine this part of the plant is used as a local anesthetic for the treatment of dysentery. The essential oil, which contains a series of monoterpenes, such as 1,8-timol, linalool, 4-terpineol, caryophyllene, lemon and so on, is described as a strong repellent against insects.

Recently in EP 568001 was described antivirus mulans (synonym bungeanum), effective to prevent thrombosis. According to JP 01294657 extraction of the pericarp (or pericarp) organic solvents gives an extract containing isobutyramide providing local anesthetic action in 30 seconds after application to the language and continuing up to 20-80 minutes.

Now unexpectedly discovered that the extract of the pericarp Zanthoxylum bungeanum, obtained by extraction with carbon dioxide under supercritical conditions, has a remarkable pain management activity without the provision of local anesthetic action, characteristic of the extracts obtained using solvents. The product of the present invention is obtained by extraction of the pericarp Zanthoxylum bungeanum, finely chopped or transformed into granules, carbon dioxide at a pressure of from 150 to 300 bar (1,510⁴kPa - 3,010⁴kPa), preferably at 180-230 bar (1,810⁴-2,310⁴kPa) at a temperature of from 35 to 55^oC, preferably at 35-40^oC.

The extract obtained can either be used as such after removal of the extraction of water or additionally be purified by separation elino n-hexane or petroleum ether.

The obtained extracts, as it turned out, have a pronounced analgesic or pain-soothing activity when applied to people subcutaneously; therefore, they are valuable for use in the pharmaceutical and cosmetic fields.

In the pharmaceutical field they are useful for pain relief in diabetic microangiopathy, hemorrhoidal pain, burns and any form of local pain. An additional application of the extracts according to the invention is the treatment of itching.

In the cosmetic field, the extracts according to the invention is useful in depilatory creams, compositions for use after sun lotions and shaving creams with all the skin treatments that require a local painkiller or antipruritic actions.

Antipruritic activity of the extracts according to the invention was evaluated using electrophysiological measurements using an experimental model in vitro preparation of the sciatic nerve - the longest muscle is the extensor (extensor) fingers (extensor digitorum longus (EDL) rats.

Used adult Sprague-Dawley rats, dead using intracardiac overdose of pentothal (Penthotal). EDL muscle with a long section of the sciatic nerve rasiklal every 10 minutes. The tested extracts, preferably with added surface active substance, was dispersible in various concentrations, thus resulting in contact with nerve fibers, neuromuscular junctions and muscle. For electrophysiological experiments, intracellular microelectrode filled with 3M KCl, were placed into the muscle cells for recording electrical phenomena (low potential end-plate potentials of the end-plate membrane potential of muscle cells) both spontaneous and evoked by stimulation of the nerve. For this purpose, the nerve was connected to a stimulator and optional stimulated once per second. Electrical phenomena in muscle cells were detected using microelectrode connected to the signal amplifier and visualized using digital cathode ray oscilloscope.

The extracts according to the invention when tested with concentrations varying from 0.0005 to 0.002%, had a strong transient activating effect on the neuromuscular synaptic transmission, as evidenced by the increasing frequency low potential end-plate and the emergence of spontaneous potentials of the endplate. On the contrary, extracts, obtained on impulse.

Analgesic activity of the investigated extracts was evaluated in 10 healthy volunteers by assessing thermal sensitivity of the skin.

Gradually heated thermal probe was placed in the shoulder area of the subject through 30 minutes after treatment with investigational product or corresponding placebo. Was measured the temperature perceived by the subject as painful. Was administered 0.5 ml of the emulsion prepared according to example VII containing 0.5% extract of Zanthoxylum bungeanum, obtained according to example I. Presented in table.1 the results show an analgesic effect of the studied extract.

The extracts according to the invention can be manufactured in the form of creams, lotions, foams, gels for application to the skin or mucous membranes, soft gelatin capsules, hard gelatin capsules, tablets, and suppositories; preferably the extract according to the invention is manufactured in the form of creams or foams for skin treatment or in the form of soft gelatin capsules, chewable tablets or suppositories for system use.

The dosage of the extract in the finished forms of the drugs vary between 5 and 100 mg per dose in preparations for systemic use, whereas in the case of drugs for m which demonstrate the invention, not limiting it.

Example I. Receiving lipophilic extract of Zanthoxylum bungeanum.

10 kg of pericarp Zanthoxylum bungeanum were extracted according to the procedure described below, in 25 l of extraction installation for supercritical gas, is equipped with two separators as a condenser for fractionation of the extract.

10 kg of the pericarp, mechanically dried after collection at a temperature not higher than 60^oWith, extrudible in the form of cubes and was extracted WITH₂under supercritical conditions under the following experimental conditions: - temperature: 35^oWith the extractor, 30^oWith the first separator and 20^oWith the second separator; - pressure: 180 bar (1,810⁴kPa) in the extractor, 100 bar (1,010⁴kPa) in the first separator and 50 bar (0,510⁴kPa) in the second separator.

The flow of CO₂was 10 liters per minute for 45 minutes. The extract was concentrated in the second separator, while the greatest part of the water present in the plant matrix, was concentrated in the first separator. After drying of the extract under vacuum in the second separator at a temperature not exceeding 40^oWith received 1.5 kg pasty extras%. Analysis of HPLC (high performance liquid chromatography) was performed on Hibar RT LiChrospher 100RP-18 column with a profile of elution (1 ml/min) are presented in table.2. Injectable quantity was 5 µl of a solution with a concentration of 2 mg/ml Chromatogram shown in the drawing.

Example II. Getting lipophilic extract of Zanthoxylum bungeanum.

10 kg of the pericarp, mechanically dried after collection at a temperature not exceeding 60^oWith, extrudible in the form of cubes were extracted and CO₂under supercritical conditions under the following experimental conditions: - temperature: 40^oWith the extractor, 30^oWith the first separator and 20^oWith the second separator; - pressure: 205 bar (2,0510⁴kPa) in the extractor, 100 bar (1,010⁴kPa) in the first separator and 50 bar (0,510⁴kPa) in the second separator.

The flow of CO₂was 10 liters per minute for 45 minutes. The extract was concentrated in the second separator, while the greatest part of the water present in the plant matrix, was concentrated in the first separator. After drying of the extract under vacuum in the second separator at a temperature not exceeding 40^oWith received 1.5 kg of paste and extract of example I, and the content of isobutylamides about 20 wt.%.

Example III. Getting lipophilic extract of Zanthoxylum bungeanum.

10 kg of the pericarp, mechanically dried after collection at a temperature not exceeding 60^oWith, extrudible in the form of cubes and was extracted WITH₂under supercritical conditions under the following experimental conditions: temperature in the extractor 40^oC and a pressure of 230 bar (2,310⁴kPa). The ratio of CO₂used for extraction of the extracted drug was 27-45 kg per kg of the drug. The extract was concentrated in the separator at 50 bar (0,510⁴kPa) at 20^oC. After drying of the extract under vacuum in the second separator at a temperature not exceeding 40^oWith received 1.3 kg pasty extract, which was faintly colored in yellow/green color and had the same physicochemical characteristics as the extract from example I.

Example IV. Obtaining purified lipophilic extract of Zanthoxylum bungeanum.

0.5 kg lipophilic extract of the pericarp Zanthoxylum bungeanum, prepared according to example I, was dissolved in 2.5 liters of 95% aqueous methanol and extracted 3 times with 0.5 l of n-hexane. The hexane phase is sterile in the methanol phase. Inactive hexane phase was removed, whereas the methanol phases were combined, diluted with 0.6 l of water and re-extracted twice with 0.6 l of n-hexane. The combined hexane phases were decolorized 0,3% charcoal, dried over Na₂SO₄and concentrated to an oil at a temperature not exceeding 40^oWith under vacuum, obtaining 0.22 kg of oily extract mediabase consistency with the content of isobutylamides about 50%.

Example V Alcohol solution Zanthoxylum bungeanum.

100 ml contains: Zanthoxylum bungeanum 20% solution in oleilove alcohol - 0,50 Cyclomethicone - 20,00 Ethyl alcohol in 100.0 ml of Example VI. Nesporova solution Zanthoxylum bungeanum.

100 ml contains: Zanthoxylum bungeanum 20% solution in oleilove alcohol - 0,50
PPG-26 Buteth 26 and PEG-40 gidrirovannoe castor oil - 5,00
Methylchloroisothiazolinone and Combination - 0,10
Purified water in required quantity before in 100.0 ml
Example VII. Emulsion Zanthoxylum bungeanum.

100 g contains:
Zanthoxylum bungeanum 20% solution in oleilove alcohol - 0,50
Isohexadecane - 5,00
Glycerin - 4,00
C_12-15alkylbenzoic - 2,00
Cyclomethicone - 2,00
PEG-20 literallayout and Literallayout - 2,00
Lanolin wax - 1,00
Acrylates/C_10-30alkylacrylate copolymer - 0,50
Cetyl alcohol - 0,5 what I salt EDTA (Ethylenediamine tetraoxane acid) - 0,10
Water as needed - Up to 100.0 ml
Example VIII. Liquid emulsion Zanthoxylum bungeanum.

100 g contains:
Zanthoxylum bungeanum 20% solution in oleilove alcohol - 0,50
PEG-20 literallayout and Literallayout - 10,00
With_10-18triglyceride - 10,00
Glycerin - 5,00
Oil from wheat germ - 2,00
Dimethicone - 2,00
PPG-25 Laureth-25 - 2,00
Cetyl alcohol - 1,00
Gidroksilirovanii lanolin - 0,50
Imidazolidinedione - 0,30
Hectorite (e) Hydroxyethyl - 0,50
Phenoxyethanol and methylparaben, and ethylparaben, and propylparaben, and butylparaben - 0,50
Tocopherol - 0,10
Water as needed - Up to 100.0 YPD

Claims

1. The extract of the pericarp Zanthoxylum bungeanum, analgesic activity, obtained by extraction with supercritical CO₂.

2. Extract on p. 1, obtained by extraction of CO₂at a temperature in the range from 35 to 55^oand under pressure in the range from 150 to 300 bar (1.510⁴to 3.010⁴kPa).

3. Extract on p. 1, containing by weight from 20 to 50% of isobutylamides.

4. Pharmaceutical composition having analgesic activity, containing as active ingredient extractivist, containing as active ingredient an extract on p. 1 in a mixture with suitable excipients.