JPS6026376B2 - Anti-psoriasis active substance and its production method - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a process for the preparation of anti-drug active substances by extraction from various fern plants, in particular their leaves and rhizomes.

Despite advances in scientific treatment, there is no known drug that can treat patients suffering from psoriasis and solve the challenges of this dermatological field related to forehead psoriasis.

The knowledge of Xiamena is very old, and many attempts have been made to treat it, but with very unsatisfactory results, and in the vast majority of cases, drugs that are only effective for a short period of time are used. is in a state of These treatments continue to be used because they are harmless to the patient and symptomatic relief is found, but they never produce a complete cure or significant improvement. This problem is getting worse as the number of psoriasis patients is increasing every day.

The dry light is genetically transmitted in such a way that it appears clearly or indistinctly in the offspring, or at least remains insidiously, and in this latter case only reveals itself when the pathological factors that cause it to appear are activated. There is a theory that it is. The whole table is affected, but one of the main areas is "dandruff"
head in the form of
Regardless of the use of topical treatments, people generally do not pay attention until they realize that their symptoms are getting worse and worse.

The presence of "dandruff" is observed in 90% of cases, if the dry light affects other areas of the skin. Thus, this disease can affect any part of the body, regardless of age. Therefore newborns as well as the elderly between the ages of 60 and 70 can be affected by it. Its geographic spread is worldwide and is independent of race, although the index is probably lower among blacks.

The complication that eventually occurs is arthropathy, which eventually affects important tissues such as the liver and kidney tissues.

In summary, psoriasis and forehead psoriasis are easily diagnosed pathological lesions, although an anatomical pathological diagnosis is required.

Conservatively, 1% of the world's population suffers from it. To date, there are no effective drugs, and patients with dry eyes can only rely on therapeutic drugs. The inventors
Natural polar fractions isolated from the rhizomes and leaves of Dryopteris cracillizoma, Polypodium vulgare Linn, Polypodium leucotomos, Phlebodium decumanan, Thiatea taiwaniana and the rhizomes of Polypodium aureum Linn and Polypodium triceriale are male , was found to have therapeutic activity in the treatment of psoriasis and psoriasis patients of women and of all ages.

This also includes derivatives thereof: esters, amides, etc. More than 300 patients suffering from psoriasis were treated orally with small doses, for example 5/9/kg body weight daily. The results showed that 80% of patients treated for about 3 months were completely cured. A double-blind trial was conducted in a group of 50 patients and showed efficacy compared to a placebo with the same organoleptic size, shape and characteristics as the drug. These fractions and derivatives have been used in all forms of xerosis and in various stages of this physiological pathology. No influence was found based on physical knowledge. During the 12 years of research, hematological tests, bone marrow, Kenzo and liver function tests and urine tests showed that
Never showed any alteration.

In accordance with the U.S. F.D.A.'s "Guidelines for Reproduction Studies and Safety Evaluation of Drugs for Human Youth"
ines's r reprodmtion study
s safety evaluation of
Fertility rates in rats and mice and mammals (dogs) were not altered by the scale forhuman vessel e'', and no malformation effects were observed in four generations of rats and mice and two generations of dogs. No pain activity was also found. These studies were carried out in mice by oral administration of 1 O/k9 body weight daily for 2 weeks. Animals were sacrificed with and without glass particles in the lumbar brain from 7 weeks onwards. The method used in this study was developed by J.
J.W. ) Brit. J. Camera Vol. 5, p. 328 (
(1951) and the statistical evaluations used were published by Arcos and his collaborators in Chemical Induction op Cancer.
ductionoICamer), Pag Academic Press Inc.
s lm. ), New York (1963 hand).

The mechanism of action of the polar fraction is a.
Increased permeability of amino acids such as saccharose, sucrose, fructose, amino acids such as valin, lysine, and small amounts of others.

b. Increased motility of cell membrane corpuscles.

c Increased water exchange in the cell hidden bell.

d Possibly related to the former, the activity of hepatocytes, which exerts its large metabolic effects, was observed.

e Increased collagen growth and maturation activity.

It has no steroid activity. Regarding its effects on other organs and systems, it has a digitalis-like bradycardic effect, which is probably due to its effect on the cell membranes of the myocardium. The process according to the invention makes it possible to carry out the extraction of polar fractions from said parts of plants in industrial yields and in useful amounts for use in pharmaceutical formulations.

For optimal yields, leaves should be collected after spore development. In one embodiment of the method of the present invention, the method comprises the following steps. Dry stalks should be made into strips of 2-3 strips, for example.
The leaves are collected and dried.

Drying is carried out, for example, by continuously feeding the raw material into a conventional dryer consisting of a rotating wire screen approximately 5 mm wide and 28 h long, which moves in a hot section at a temperature not higher than 70.degree. Approximately 0.5 tons of wet raw material can be dried per hour by adjusting the speed of the rotary deposit. Forehead granulation Dry raw material (residual moisture 8% or less) is adjusted to produce two-skin particles and made into jaw granules in a disc mill.

Extraction-Evaporation This can be carried out with any solvent (relativity 1.890-9.0%), preferably methanol in a ratio of 1:4 by volume.

It is evaporated, leaving behind a retentate corresponding to 1/5 of its original volume.

Purification 1 The semi-solid residue of the extraction-evaporation is partitioned into the immiscible solvent system N-hexane/water (10:4) and left in a shaker overnight to separate the lipids and resins in the hexane phase.

2 Pass the separated and filtered aqueous solution through an exchange column.

3 Add Ca(OH)2 to neutralize.

4. Add activated carbon to the above solution in portions until the solution becomes clear.

5 Evaporate this solution to 1/10 of the original volume,
Precipitation in an anhydrous organic liquid miscible with water, such as a CK-free alcohol.

6. The precipitate is subjected to a suction oven to obtain a first powder mass, and the mother liquor is evaporated to obtain a second powder mass.

The powder is dried under reduced pressure until very white.

The second white crystalline mass, which is the object of the present invention, is not a definite ordinary substance, but is a composition determined by the pharmaceutical properties used and the method of extraction and purification.

The presence of a total amount of 70% D-glucose and D-fructose was found as a result of routine qualitative tests and single and complete characterization of the corresponding acetyl derivatives.

On the other hand, the presence of acid compounds that cannot be easily separated from sugars is detected by chromatography as well as conventional spectroscopy. The pharmaceutical compositions of the present invention are prepared in a dilute dosage form by admixing the polar fraction with a pharmaceutical carrier according to accepted pharmaceutical techniques.

The resulting pharmaceutical composition constitutes an object of the present invention. The active ingredient, or polar fraction, is present in the compositions of the present invention in an amount sufficient to provide anti-dry lacquer activity. Preferably, the compositions of the present invention contain about 10 to 100 9 active ingredients per unit dose.

Pharmaceutical carriers can be, for example, solid or liquid. Lactose, magnesium stearate, albater Q, sweet potato loin, talc, stearic acid, gelatin, agar, pectin, gum arabic,
Aerosil and the like are examples of carriers. Examples of liquid carriers are alcohol (such as ethanol or propylene glycol), water with a solubilizing agent such as polyethylene glycol), peanut oil, olive oil, and the like. The carrier or diluent can include a retarding agent, such as glyceryl monostearate or glyceryl distearate, optionally with a wax. A wide variety of pharmaceutical dosage forms can be used.

That is, when a body carrier is used, it can be formulated into a tablet, put into a hard gelatin capsule in the form of a powder or pellets, or a troche form can be selected. The amount of carrier varies widely but is approximately 25 to 300
Double 9 is preferred. If a liquid carrier is used, the preparation can be a syrup, emulsion, soft gelatin capsule, suspension or liquid solution, eg, in an ampoule, as a sterile injectable solution for parenteral use. Pharmaceutical compositions of the invention that are liquid suspensions or solutions do not encompass mere suspensions or solutions of the active ingredients in common solvents that are not suitable for internal use.

Another object of the present invention is to provide tablets, capsules, troches, liquids for internal administration, which are capable of producing anti-inflammatory activity and comprising a pharmaceutical carrier and an amount of polar fraction sufficient to produce said activity. The dosage unit is provided in the form of a suspension or a sterile injectable solution.

Administration can be oral or parenteral, with oral administration being preferred. The active ingredient is in a daily dose of approximately 50-500
Preferably, it is administered in females. Advantageously, doses corresponding to 1 to 4 times per day are administered. Anti-psoriasis activity is obtained when administration is as described above. Since psoriasis is a chronic, insidious disease with a genetic etiology, it is preferable to use it in capsule or tablet form to maintain a stable in-dish concentration and allow continuous activity of the drug.

Undoubtedly, in the case of treatment of heaviness caused by other drugs or by the disease itself, as in the case of steroids, intravenous injections or a continuous drip of serum may be given to avoid a critical situation. can. It goes without saying that for children, drops or emulsions can be used, and for adults with damage to the upper gastrointestinal tract, suppositories can be used.

Pharmaceutical compositions are manufactured into the desired composition by conventional techniques such as mixing, granulating and, if necessary, tabletting, or by mixing and dissolving the appropriate ingredients. Next, an example will be given and explained.

Example 1 M. Dried leaves 12k9 granulated with 10 stripes (2.5 skins)
1. Extract with 95% ethanol for 48 hours for 70 minutes.

The residue was added to a mixture of n-hexane/water (at 15:10) and left overnight in a broiler. Separate the hexane phase and filter the aqueous phase. The furnace liquor is passed through an exchange column and then neutralized with alkali.

The thus neutralized solution is clarified and evaporated under moderate vacuum for 4 hours until almost dry (yield: approximately 15 females).
.

The dried solid is redissolved in methanol and crystallized overnight at 40°C.

Example 2 Disc mill, M. Dried plant 36k9, granulated with 10 strips (2.5 kites), is extracted with n-hexane for 1 hour at room temperature.

The hexane solution is concentrated and left in water in a separator overnight.
Separate the hexane phase and evaporate the aqueous phase. Take the hexane-extracted plant residue in a sufficient amount of hot ethanol and leave it overnight to prepare a saturated extract.

The solution is filtered, converted into an aqueous phase, and passed through an exchange column. The solution is then neutralized, clarified and evaporated to almost dryness.

The solid is redissolved in 70% ethyl alcohol and crystallized overnight at room temperature.

Separate the crystals, evaporate the supernatant (yield: 18 females) and dry under reduced pressure. Example 3 Disc mill, M. Dried rhizomes 12k9, granulated with 10 rings (2.5 ribs), are continuously extracted with chloroform at room temperature.

This is concentrated and redissolved in a mixture of n-hexane and water.
Separate the hexane phase and evaporate the aqueous phase. The extracted rhizome residue was taken up in hot methanol and allowed to stand for 16 hours.

This is filtered through a furnace and passed through an exchange column. The extract is neutralized, clarified, evaporated and placed in 95% ethanol in a crystallizer overnight. The crystals are separated, the supernatant is evaporated and then dried under reduced pressure (yield: milk lamp). Example 4 1. Granulated dried plants (M.1 seat, 2.5 sides) are extracted with 90% methanol at 70% by refluxing for an hour.

The extract is filtered and evaporated, taken up in a mixture of hexane/water (3:2) and allowed to stand, the hexane is separated off and the aqueous phase is filtered and evaporated.

The residue is dissolved in 90% hot ethanol and passed through an exchange column.

The extract is neutralized, evaporated to 1/10 of its original volume, cooled and crystallized.

The crystals are separated by filtration and the supernatant liquid is dried under reduced pressure (yield: 240-25 females).

The following examples of pharmaceutical formulations are intended to be illustrative rather than limiting.

Example 5 Ingredients Quantity Polar Fraction 40% Lactose 60% Female Ingredients are mixed and strained into hard gelatin capsules.

Capsules prepared as described above are administered three times per day. Example 6 Ingredients Quantity Polar fraction 60 Female starch 60 Female talc 5 Orin 5mc Polyvinylpyrrolidone 5p The fraction and starch are mixed and granulated with a 10% gelatin solution containing polyvinylpyrrolidone.

The grains are knotted, dried and then mixed with kaolin and talc. This is strained and converted into tablets. As understood from the above description, the method for producing the anti-dry hawk active substance according to the present invention is specifically carried out as follows. Dryopteriscrassirhizoma,
Polypodium vulgare. Lin (Polyp iumv
Gare, Linn), Polypodium leucotomos (Polypodium leucotomos), Phlebodium decumnan zei, Smith (Phleb side um
DeC plate anun J, Smith), Polypodium decuman (Polypium Decuman skin)
, theataiwan of C.
iana), Polypodium aureum phosphorus (Pol
yp's imm ame mountain mLinn) or Polypodium triseriale (PolyP's iumtriserj
Ale) rhizomes cut into 2-3 strips or leaves of the former six are subjected to a drying process at a temperature not higher than 70°C, and the dried raw material with a residual moisture content of 8% or less is granulated into particles with a diameter of 2. Below the field, particles with a density of about 0.1 to 0.80 are formed, and a dielectric constant of 1.890 to 9. Extraction was carried out with a female solvent, and the semi-solid residue obtained by evaporating the solvent was taken up in n-hexane/water (10:4), and this was left overnight in a separator to separate the aqueous phase. Then, the aqueous solution was passed through the exchange resin, Ca(OH)
Add 2 to neutralize it, add activated carbon little by little until the solution becomes clear, then evaporate it back to 1'10, precipitate with absolute alcohol, filter the precipitate in a suction oven, and remove water. Evaporate again to obtain a second powdery mass, which is dried under reduced pressure until a white solid is obtained.

Claims (1)

[Claims] 1. Dryopteris crassirhizoma
), Polypodium vulgare Linn (Polypodium
um vulgare, Linn), Polypodium leucotomos (Polypodium leucotomos)
s), Phlebodium decmannan zei-smith (Ph.
iebodium Decumanun J. Smit
h), Polypodium demanan (Polypodium
m Decumanun), Thiatea taiwaniana (
Cyathea taiwaniana), Polypodium aur
eum Linn) or Polypodium triseriale with a solvent with a dielectric constant of 1.890 to 9.08, concentrating the extract, taking up the concentrated residue in n-hexane/water, and recovering the aqueous phase. A method for producing a characteristic anti-psoriatic (including psoriasis-like) active substance. 2. The manufacturing method according to item 1, which involves extracting the rhizome of a plant. 3. The manufacturing method according to paragraph 1, which involves extracting plant leaves. 4. Drying the rhizomes or leaves at a temperature not higher than 70°C until the residual moisture content is 8% or less, and then extracting.
The manufacturing method according to any of Item 3. 5. The manufacturing method according to item 4, wherein the dry product is made into granules with a diameter of 2 mm or less and a density of 0.1 to 0.80, and then extracted. 6 Pass the aqueous phase through an exchange resin, neutralize it by adding Ca(OH)_2, treat it with activated carbon until it becomes clear, precipitate it with absolute alcohol after concentration, collect the precipitate, and add it under reduced pressure. The manufacturing method according to any one of Items 1 to 5, wherein the method is dried.