Self-emulsifying system of butylphthalide drug delivery, method of system obtainment and application

FIELD: medicine.

SUBSTANCE: invention concerns medications, particularly self-emulsifying system of butylphthalide drug delivery, including 1% to 65% of butylphthalide, 10% to 65% of emulsifying agent, and filler. Emulsifying agent is a mix of polyoxyetylene castor oil and polyethyleneglycol-8-glycerin caprilate/caprate, where polyoxyethylene castor oil to polyethyleneglycol-8-glycerin caprilate/caprate ratio is 1:0.5 to 1:1.5. Invention also concerns medication containing claimed delivery system, and method of system obtainment.

EFFECT: faster achievement of maximum butylphthalide concentration, increased maximum concentration, improved butylphthalide stability.

9 cl, 1 dwg, 3 tbl, 18 ex

 

The present invention relates to a new system of delivery and release of drugs butylphthalide and, in particular, to a self emulsifiable delivery system drug butylphthalide and its preparation and use in pharmaceutical compositions.

The LEVEL of TECHNOLOGY

Offering self-emulsifying delivery system drugs (SEDDS) is a solid or liquid dosage form, containing an oil phase, surfactant and auxiliary surfactant, differs primarily from the fact that this dosage form may spontaneously forming emulsion of oil-in-water" in the gastrointestinal tract or at ambient temperature (generally related to body temperature, namely 37°C) with moderate stirring. With a growing number emulsifying substances such self emulsifiable system can spontaneously form a microemulsion in the gastrointestinal tract and thus it is called sonomicrometry delivery system drugs (SMEDDS). When hit SEDDS in the gastrointestinal tract it first samoemulgirutisa in the form of droplets of the emulsion and spreads rapidly through the GI tract, thereby reducing the irritation caused by direct contact Lakers the governmental funds to the mucous membrane of the gastrointestinal tract. In the gastrointestinal tract structure of microparticles emulsion will change or be destroyed. Thus formed microparticles micrometer or nanometer level can penetrate into the mucous membrane of the gastrointestinal tract, and digested fat drops into the blood stream, thereby greatly improving the bioavailability of the drug. Offering self-emulsifying delivery system of the medicinal product is mainly used in relation to fat soluble and less soluble drugs. It can improve the stability and bioavailability of drugs.

Butylphthalide is a major component of shelterees and their seeds. It is possible to get a direct extraction from natural oil of celery seed or synthesis. In the Chinese patent for invention № 98125618.X described the use of L-n-butylphthalide in the manufacture of antithrombotic and preventing agglutination of platelets medicines, clearly showing that L-n-butylphthalide can regulate the function of the system NOS-NO-cGMP and arachidonic acid metabolism in neuronal cells after cerebral ischemia. In the Chinese patent for invention № 93117148.2 described the use butylphthalide in the manufacture of a medicine for the prevention and treatment of disorders caused by cerebral ischemia in MLEKO the melting or person, where specified butylphthalide is a liquid oil without optical activity. He has an intense aroma of celery and has the following formula:

Currently butylphthalide commercially available only in the form of soft capsules, that is butylphthalide dispersed in vegetable oil and then immediately fill them soft capsules. Although this dosage form may hide an unpleasant odor substances, but its content is poorly dispersed in the aqueous phase and the degree of dissolutionin vitroit is impossible to directly determine that not only prevents the quality control during the manufacture of the product, but also significantly affects the absorption rate of the medication.

In addition, the Chinese patent for invention № 02123000.5 the authors of the present invention has described a method of improving the solubility in water butylphthalide through the inclusion of a derivative of cyclodextrin. This method not only hid the odor, but also increased the solubility butylphthalide. However, the number of primary component used in the process of obtaining the included substances is limited by the volume of the dosage form and thus it is impossible to ensure different dosage forms to meet the needs of the PAC the clients. For example, getting in solid dosage capsules limited filling ability, the reception of tablets is limited by the suitability of the size of the tablets, and the number of primary components in the included substances can not be too large. Moreover, method of use, consumes more power, has a large number of process steps, is more difficult to control and requires more parameters to control the process (such as temperature, type and volume of grinding, time, speed and duration of mixing). Thus, industrialization technologies enable the specified product is relatively slow.

DISCLOSURE of INVENTION

The present invention is to overcome the drawback of the above drugs butylphthalide when used in the clinic and the provision of a new system of delivering medicines for butylphthalide, i.e. offering self-emulsifying delivery system drug butylphthalide.

Offering self-emulsifying delivery system drug butylphthalide related to the present invention contains, as main components from 1 to 65 wt.% butylphthalide, from 10 to 65 wt.% emulsifying agents and preferably contains as main components 10 on the 50 wt.% butylphthalide, from 15 to 60 wt.% emulsifying substances, respectively, together with different fillers depending on the desired dosage forms to obtain the appropriate dosage forms, where appropriate amount of used fillers is from 0 to 85%, preferably from 5 to 75% (each of the above quantities are based on the total weight offering self-emulsifying delivery system medicines for butylphthalide).

Butylphthalide selected from the group consisting of his racemic, levogyrate and programada isoforms.

Offering self-emulsifying delivery system of the medicinal product according to the present invention is also suitable for delivery to an oil-soluble derivatives butylphthalide.

In the present invention preferably emulsifying substances SEDDS are non-ionic emulsifying agents. Non-ionic emulsifying agents are less toxic than ionic emulsifying substances, and cause only reversible changes in the permeability of the mucosa of the gastrointestinal tract. Emulsifying substances SEDDS of the present invention is selected from any of the group consisting of liquid or solid glycerides of ethoxypropionitrile, oleate of polyoxyethylene, liquid lecithin (for example, Ophase 31, HLB=4,0), polyoxyethylene castor oil (cremophor EL, HLB=13,5), coconut oil, glycerides is poliatilenglikola (labrafil CM10, HLB=10), glycerides of polyethylene glycol and oleic acid, almond oil (labrafil M1944CSD, HLB = 3 to 4; labrafil M2125CS, HLB = 3 to 4), trioleate polyoxyethylene(25)glycerin (tagat TO, HLB=11,3), oleate polyoxyethylene(20)sorbitan (tween 80, HLB=11,0), kaprilat/caprate the polyethyleneglycol-8 glycerin (Lubrizol, HLB=14), and the like, or mixtures of any two or more of these.

The method of obtaining: emulsifying substances completely melted in a water bath of 20 to 60°C and mix, then add butylphthalide under stirring and add fillers to obtain a dosage form offering self-emulsifying delivery system drug butylphthalide.

The present invention also refers to a series of compositions for the delivery of self emulsifiable medicines butylphthalide and different dosage forms butylphthalide with the delivery mechanism self emulsifiable medicines, together with fillers, suitable for the respective dosage forms such as tablets, soft capsules, granules, hard capsules and oral liquid for delivery offering self-emulsifying drug butylphthalide.

Offering self-emulsifying delivery system medicines for butylphthalide of the present invention is particularly suitable for the dosage form in the form of soft capsules, whose soda the way, is a liquid oil having the property of savemarriage, which contains butylphthalide, emulsifying agent and, optionally, a filler. Fillers selected from any of the group consisting of vegetable oils, for example sesame oil, corn oil, peanut oil, soybean oil, almond oil, oil of seeds of peach, cottonseed oil, sunflower oil and olive oil or a mixture of any two or more of these. Optionally, the dosage form may also contain antioxidant and lipophilic flavoring.

The fillers contained in the self emulsifiable soft capsules of the present invention may be conventional fillers in this area. Offering self-emulsifying delivery system drug butylphthalide of the present invention may also be suitable for the dosage form oral liquid, which is a liquid oil having the property of savemarriage and which can be entered after dilution with water. In the above-mentioned self emulsifiable delivery system drug butylphthalide directly for oral fluid can also add water, solubilizing agents and suitable flavoring agents.

Offering self-emulsifying delivery system drug butylphthalide of the present invention m is may also be suitable in the form of oral solid powders or granules. Oral solid formulations offering self-emulsifying delivery system drug butylphthalide of the present invention, such as tablets (including capsules with prolonged action and controlled-release tablets), capsules (including capsules with prolonged and controlled release), granules and the like, can be obtained by conventional methods in accordance with the requirements for oral solid formulations include excipients, such as loosening, binders, flavorings and/or polymeric basic substances, etc. in the above-mentioned self emulsifiable delivery system drug butylphthalide, resulting in a solid powders or granules with property savemarriage.

Tablet offering self-emulsifying delivery system drug butylphthalide according to the present invention can be obtained by mixing solid powders or granules capable of samomoderirovanie, with suitable pestiferously substances, loosening and lubricants, and followed by pressing in the form of a suitable size. If necessary, the tablets can be coated with a suitable coating, such as a stomach coating, enteric coating or coating for prolonged or controlled release dosage cf is DSTV, including cellulose acetate, ethylcellulose etc.

Hard capsules offering self-emulsifying delivery system drug butylphthalide according to the present invention can be obtained by a combination of solid powders or granules capable of samomoderirovanie, with conventional lubricants, agents for controlled release and so on, resulting in a hard capsule or capsule with prolonged action or controlled release.

The contents of the self emulsifiable soft capsules of the present invention is an oily liquid, able to samomoderirovanie. When the capsules disintegrated in water, the drug is rapidly dispersed in water, forming an emulsion of the oil-in-water". As a result, the product quality can be evaluated test for dissolution. In addition, the contact area butylphthalide from the gastrointestinal tract is greatly increased, thus increasing the absorption rate of the medication. Offering self-emulsifying delivery system of the medicinal product according to the present invention can be obtained by using one-step and easily managed process. Moreover, it has the advantages of low energy consumption during its manufacture, or the method of preparation and a high degree of industrialization, etc.

Self emulsifiable soft capsules butylphthalide have properties disguise his strong peculiar smell in the usual soft capsules, ease of administration, ease of swallowing and good endorsement patients. Moreover, they allow oily active ingredients quickly dispergirujutsja upon contact with gastric juice, forming an emulsion of the oil-in-water, thereby increasing the degree and rate of absorption. Test acceleration and long-term test for this part it is shown that although the aging shell of this soft capsules significantly at elevated temperature and increases the time of disintegration, it is still less than 60 minutes and thus complies with the provisions of the Chinese Pharmacopoeia. Different parameters such as appearance, content, degradation products, time to salaamullahi and the degree of release ofin vitrothis composition changed slightly.

BRIEF DESCRIPTION of DRAWINGS

The drawing shows the result of the distribution of particle size system savemarriage butylphthalide when measuring laser analyzer of the distribution of particle size. Here you can see that more than 98% of the droplets in the emulsion have a particle size less than 5 μm and, thus, this system belongs to sonomicrometry delivery system Le is artenova funds. You can conclude from the graph percentiles for volume (see)that the distribution of particle size in this system is narrow and uniform.

DETAILED description of the INVENTION

Soft capsule used in the present invention as the preferred dosage forms offering self-emulsifying delivery system drug butylphthalide.

The contents of the soft capsules for the delivery of self emulsifiable medicinal product according to the present invention contains butylphthalide and emulsifying substance, preferably in the following wt.%: from 10 to 50 butylphthalide and from 15 to 60 specified emulsifying agent. In the oily liquid medicines may also add a suitable antioxidant, such as dibutylaminoethanol and flavouring substance, such as peppermint oil, green Apple, etc.

Emulsifying agent is preferably a mixture of polyoxyethylene castor oil and kaprilat/caprate the polyethyleneglycol-8 glycerin preferably in a ratio of from 1:0.5 to 1.5 (by weight). Attitude butylphthalide to emulsifying substance, preferably from 1:0.5 to 1.5 (by weight).

The preferred method of receipt: hydrogenated castor oil properly melted in a water bath of 25°to 50 ° C, then add kaprilat/capret floor is a glycol-8-glycerine and mix with shaking to obtain a homogeneous transparent oily liquid. Add butylphthalide and mixed by shaking at room temperature. So get the contents of the soft capsules.

The soft shell capsules offering self-emulsifying delivery system of the medicinal product according to the present invention consists essentially of the composition of the shell, the plasticizing agent and water in the ratio by weight of from 1:0.2 to 0.4:0.8 to 1.3. Moreover, the shell can also include a suitable preservative, such as ethylparaben, methylparaben or their mixture.

The composition of the shell may be gelatin, gum acacia or their mixture.

Plasticizing substance may be glycerin, sorbitol or a mixture.

Real soft capsule butylphthalide can be made common ways to obtain soft capsules, such as the way of manual compression molding method of the rotary compression molding, or casting. Typically, compression methods, such as the way of the rotary compression molding, applied using an automatic rotary machine for seaming capsules, with the temperature controlled in the range from 40 to 50°C so that each soft capsule contains pharmaceutically acceptable number butylphthalide.

The following examples are shown to describe embodiments of us who oedema invention. They are not intended to limit the scope of the present invention.

Example 1: obtaining a self emulsifiable soft capsules butylphthalide

Obtaining solution of gelatin: use 100 g of gelatin, 30 g of glycerol, 130 g of water and 200 mg of ethylparaben. To gelatino add appropriate amount of water, allowing it to absorb water and swell. Glycerin, ethylparaben and the remaining water is placed in a container and heated to a temperature of from 70 to 80°C and stirred to homogeneity. The swollen gelatin added with stirring, melt, incubated for 1 to 2 hours and left alone to the floating foam. Surfaced foam then clean off and the residue is filtered through a clean white cloth and keep warm for later use. The viscosity of the obtained adhesive liquid is generally from 2.8 to 3.2 degrees.

Getting oily liquid with butylphthalide: 100 g butylphthalide, 50 g of each of the kaprilat/caprate polyethylene glycol-8-glycerol and polyoxyethylene castor oil are weighed and thoroughly mixed to obtain oily liquid.

Pressing soft capsules: the gelatin-glycerin and oily liquid with butylphthalide placed in automatic rotary machine for seaming capsules and keep the temperature from 40 to 50°C. Soft capsules, each containing 200 mg of oily liquid, incaps lyout.

Soft capsules have the proper size in appearance and good texture content in the measurement.

Example 2: Confirmation of method of obtaining a self emulsifiable soft capsules butylphthalide

Obtaining solution of gelatin: use 1000 g of gelatin, 300 g of glycerol, 1300 g of water and 2000 mg ethylparaben. To gelatino add appropriate amount of water, allowing it to absorb water and swell. Glycerin, ethylparaben and the remaining water is placed in a container, heated to a temperature of from 70 to 80°C and stirred to homogeneity. The swollen gelatin added with stirring, melt, incubated for 1 to 2 hours and left alone to the floating foam. Surfaced foam then clean off and the residue is filtered through a clean white cloth and keep warm for later use. The viscosity of the obtained adhesive liquid is generally from 2.8 to 3.2 degrees.

Getting oily liquid with butylphthalide: 1000 g butylphthalide, 500 g of each of the kaprilat/caprate polyethylene glycol-8-glycerol and polyoxyethylene castor oil are weighed and thoroughly mixed to obtain oily liquid.

Pressing soft capsules: thus obtained gelatin-glycerin and oily liquid with butylphthalide placed in automatic rotary machine for seaming capsules and support pace is the atur from 40 to 50°C. Soft capsules, each containing 200 mg of oily liquid encapsulate.

In the soft capsule obtained in the above ratios, have a suitable appearance and good texture content in the measurement.

According to the method according to example 2 has received three series of samples. The consistency of the solution and the particle size was investigated for the three series of samples. The degree of dissolution and particle size was determined as follows.

Test solubility: these soft capsules are tested according to the test on solubility (Appendix X C: Method 2, in the Chinese Pharmacopoeia, 2005 edition, Part II), in which 900 ml of water used as solvent, and set the rotation speed 100 rpm Testing is carried out, as described. After 45 minutes, 10 ml of solution is separated and filtered. 5 ml of the filtrate is carefully removed and transferred into a 10 ml measuring flask. Methanol is added in the flask to the mark for cultivation and shaken to homogeneity. The absorption at a wavelength of 280 nm determined spectrophotometrically (Appendix IV A, in Chinese Pharmacopoeia, 2000 edition, Part II). 25.0 mg control sample butylphthalide carefully weighed and placed into a 50 ml measuring flask, add methanol to dissolve and diluted to the mark, then mixed to homogeneity. 5 ml of the solution is carefully selected and placed in 50 ml of m is th vial, then add 20 ml of methanol. Water is added into the vial up to the mark for cultivation and shaken to homogeneity. The resulting solution was used as a control and measured by the same method. Calculate the solubility of each capsule, the results are shown in table 1.

Analysis of the distribution of particle size:

use the analyzer particle size of the model Nano ZS MALVERN.

Protocol: the contents of these capsules are taken, diluted 100 times artificial gastric juice and used as a solution for testing. Aliquot of 1 ml was placed into the sample. The measurement is carried out at a set temperature of 25°C. the Range of the distribution of particle size and the cumulative distribution analyzed using unimodal statistics. The results are shown in table 2 and in the drawing.

Microscopic analysis: select an aliquot of 0.2 ml of oily liquid and added dropwise to 100 ml of artificial gastric juice at 37°C with moderate stirring. Immediately, spontaneously formed a homogeneous emulsion oil-in-water". 10 μl of the thus formed emulsion is placed on a glass slide for microscopic examination.

Statistically 98,7% of the droplets of the emulsion have a particle size less than 5 microns, which is essentially consistent with the results of the measurement distribution is possible particle size analyzer MALVERN and lies within microemulsion. Thus, it was designated as a self emulsifiable (sonomicrometry) delivery system drug butylphthalide, based on the characteristics of this dosage form.

Table 1
Results from the three series of samples in the test for solubility
ItemDissolution, %Note
Savemarriage (45 min)031201031202031203With the disintegration of the contents upon contact with water spontaneously forms a homogeneous emulsion. Samples can directly be taken to measure
100,0199,6the 98.9
Conventional soft capsule (60 min)95,496,892,5With the disintegration of the oil droplets stick to the wall of the vial or float on the surface without dispersion. The analysis can only be performed when the emulsifying agent added in with the food for dissolution
Conclusion 2Self emulsifiable composition dissolves more uniformly and quality can be controlled

Table 2
The distribution of particle size measured for the 3 series sample
The size of the particlesThe distribution of particle size %Note
031201031202031203
>5 μm2,783,052,54Just counted 300 particles on the series
from 1 to 5 micronswith 4.645,645,01
<1 μm92,6891,3192,45
Conclusion 1All three series of samples are offering self-emulsifying delivery systems for medicines

Experimental data the e stability of these soft capsules are shown in table 3:

Table 3
A preliminary test on the stability of self emulsifiable soft capsules butylphthalide
ConditionsAppearanceContent (wt.%)Product degrad.
(wt.%)
Time savemarriage (C)Release in vitro (wt.%)The disintegration time
Time (month)
The starting point0Yellow transparent soft capsule100,30,612,3399,35'50”
Test acceleration1Yellow transparent soft capsule101,10,66to 2.67100,26'45”
2Yellow transparent soft is apsule 99,30,633,3399,614'10”
3Yellow transparent soft capsule98,40,623,5100,228'30”
6Yellow transparent soft capsule99,00,583,3398,549'52”
Room temp.1Yellow transparent soft capsule100,10,632,50100,56'15”
3Yellow transparent soft capsule101,00,672,50the 98.98'35”
6Yellow transparent soft capsule 99,40,66to 2.67100,19'45”

12Yellow transparent soft capsuleof 99.10,622,8399,717'50”

Example 3: Obtain soft capsules butylphthalide

100 g butylphthalide, 50 g of each of the kaprilat/caprate polyethylene glycol-8-glycerol and polyoxyethylene castor oil, weighed, subsequent stages are the same as in example 1, except that when getting oily liquid impose additional solubilizers substance, such as 20 g of propylene glycol, and mix thoroughly. Each of the finished soft capsules contains 220 mg of oily liquid with butylphthalide.

Example 4: Obtain soft capsules butylphthalide

Obtaining solution of gelatin: use 100 g of gelatin, 40 g of glycerol, 120 g of water and 200 mg of ethylparaben. A solution of gelatin receive the same Protocol as in example 1.

Getting oily liquid with butylphthalide: 500 g butylphthalide, 600 g of kaprilat polyethylene glycol-8-glycerol and 500 mg ar is matisyohu substances orange weighed and thoroughly mixed to obtain oily liquid.

Pressing soft capsules: Method same as in example 1 except that each of the finished molded soft capsules contains 220 mg of oily liquid with butylphthalide.

Example 5: Obtain soft capsules butylphthalide

Getting oily liquid with butylphthalide: 100 g butylphthalide, 65 g of kaprilat/caprate the polyethyleneglycol-8 glycerin and 50 g of polyoxyethylene castor oil are weighed and mixed to homogeneity, receiving transparent oily liquid.

Obtaining solution of gelatin: use 100 g of gelatin, 30 g of glycerol, 120 g of water and 20 g PEG400. The Protocol for obtaining the solution of gelatin is the same as in example 1.

The stages are the same as in example 1 except that each of the finished soft capsules contains 210 mg of oily liquid with butylphthalide.

Example 6: Obtain soft capsules butylphthalide

100 g butylphthalide, 40 g kaprilat/caprate the polyethyleneglycol-8 glycerin and 50 g of polyoxyethylene castor oil are weighed and thoroughly mixed to obtain a transparent oily liquid.

Obtaining solution of gelatin: use 100 g of gelatin, 40 g of glycerol, 120 g of water and 10 g PEG400. Method to obtain solution of gelatin is the same as in example 1.

Other stages operate in the same manner as in example 1, except that each of goto is s soft capsules contains 190 mg of oily liquid with butylphthalide.

Example 7: Getting self emulsifiable granules butylphthalide

100 g butylphthalide, 100 g of kaprilat polyethylene glycol-8-glycerol, 20 g of ethanol, 100 mg peppermint oil and 100 mg flavoring orange mixed together to be used as the binder, then add to the mixture of 450 g of sugar powder and 5 g nitrosamines cellulose (L-HPC). The resulting mixture granularit and dried.

Example 8: obtaining a self emulsifiable granules butylphthalide

100 g butylphthalide, 50 g of kaprilat polyethylene glycol-8-glycerol, 50 g of hydrogenated castor oil, 100 mg peppermint oil and 100 mg of the flavor of green Apple mixed together to be used as a binder, and then added to a mixture of 400 g of sugar powder, 100 g of PVP and 5 g nitrosamines cellulose (L-HPC). The resulting mixture granularit through sieve No. 20, dried and spread on the packages.

Example 9: obtaining a self emulsifiable tablets butylphthalide

100 g butylphthalide, 50 g of kaprilat the polyethyleneglycol-8 glycerin and 40 g of hydrogenated castor oil are mixed together to be used as the binder, then add to the mixture of 100 g sugar powder, 40 g of sodium carboxymethyl amylum and 150 g of microcrystalline cellulose. The resulting mixture granularit through sieve No. 32 and you shall sutured at 45°C. Then additionally add 5 g of magnesium stearate as a lubricant and a solid powder essence green Apple as a flavoring and mix. Then the pill form of pressing, each with a weight of approximately 0,49,

Example 10: Getting self emulsifiable tablets butylphthalide

The inside of tablets: 100 g butylphthalide and 50 g of kaprilat the polyethyleneglycol-8 glycerin are mixed together as the binder, then add to the mixture of 100 g sugar powder, 40 g of sodium carboxymethyl amylum and 150 g of microcrystalline cellulose. The resulting mixture granularit through sieve No. 32 and dried at 45°C. Optionally, add 5 g of magnesium stearate as lubricant and mix. Then the pill form of pressing, each with a weight of approximately 0,49,

Coating: 60 g hydroxypropylmethylcellulose dissolved in 1000 ml of 80% ethanol. Add 0.5 g of green food coloring and mix. The coating shall be implemented by way of rolling in the floor with the temperature of the layer of tablets from 35 to 45°C, resulting in a light green tablet with a film coating.

Example 11: obtain a self emulsifiable tablets butylphthalide delayed release

100 g butylphthalide, 50 g of kaprilat polyethylene glycol-8-glycerol, 50 g of hydrogenated Castoro the oil and 100 mg of peppermint oil mixed together as the binder, then slowly add in a mixture of 100 g of hydroxypropylmethylcellulose (receiver arrayK100M), 80 g hydroxypropylmethylcellulose (receiver arrayK4M) and 10 g of ethyl cellulose. The resulting mixture is stirred to homogeneity, granularit through sieve No. 32, dried at 45°C and then sorted by size through sieve No. 20. Add 5 g of magnesium stearate as lubricant and then tablets are pressed.

Example 12: obtaining a self emulsifiable tablets butylphthalide controlled release

The inside of tablets: 100 g butylphthalide and 50 g of kaprilat the polyethyleneglycol-8 glycerin are mixed together, then added to the powder mixture of 120 g of starch, 180 g of microcrystalline cellulose, 100 g of lactose and 20 g poloxamer-188. The resulting mixture is stirred to homogeneity, granularit through sieve No. 32, dried at 45°C and are sorted by size through sieve No. 20. Add 5 g of magnesium stearate as lubricant. And then the tablets are pressed and cover composite film is from 0.1 to 0.3 mm from hydroxypropylcellulose-polyethylene acetate.

Example 13: Getting self emulsifiable hard capsules butylphthalide

50 g butylphthalide and 20 g of kaprilat the polyethyleneglycol-8 glycerin are mixed together. Then add 100 g of starch as absorbent and diluting substance, 10 g polyethylenepropylene (PVP) as a binder is about substance and 10 g nitrosamines cellulose (L-HPC) as a powder. The resulting mixture granularit through sieve No. 32, dried at 45°C and are sorted by size through sieve No. 20. Then add the magnesium stearate as lubricant and granules spread on the shells No. 1 for capsules.

Example 14: Getting self emulsifiable hard capsules butylphthalide

50 g butylphthalide and 20 g of kaprilat the polyethyleneglycol-8 glycerin mixed with 40 g poloxamer, 60 g of maltodextrin, 60 g of microcrystalline cellulose and 8 g of sodium carboxymethyl amylum. The resulting mixture granularit through sieve No. 32, dried from 45°C to 50°C and are sorted by size through sieve No. 20. After adding talc as lubricant and mixing the granules spread on the shells No. 2 for capsules.

Example 15: Getting self emulsifiable capsules butylphthalide delayed release

100 g butylphthalide, 50 g of kaprilat polyethylene glycol-8-glycerol, 50 g of hydrogenated castor oil, 100 mg peppermint oil and 100 mg of oil green Apple mixed together as the binder, then slowly add in a mixture of 100 g of hydroxypropylmethylcellulose (receiver arrayK100M), 80 g hydroxypropylmethylcellulose (receiver arrayK4M) and 10 g of ethyl cellulose. The resulting mixture is stirred to homogeneity, granularit through sieve No. 32, dried at 45°C and then sorted by size through sieve No. 20. After adding the Oia 5 g of magnesium stearate as lubricant and mixing the granules spread on the shells No. 1 for capsules.

Example 16: Getting oral fluid (oil) with a self emulsifiable butylphthalide

100 g butylphthalide, 50 g of kaprilat polyethylene glycol-8-glycerol, 50 g of hydrogenated castor oil, 0.1 g of orange flavor and 0.1 g of peppermint oil mixed, then added to 5 l of an aqueous solution containing 1% aspartame and 0.01% ethylparaben sodium, prior to the formation of emulsions of oil-in-water". The resulting solution was poured into vials of 5 ml, 10 ml, 20 ml or 50 ml for oral administration, depending on the needs of the patients.

Example 17: Getting oral oily liquid with a self emulsifiable butylphthalide

The personnel get essentially the same way as in example 16, except that the antiseptic substance, such as ethylparaben and aspartame (before adding aspartame can first be atomized in a small amount of alcohol), are added during the preparation of the oily liquid. Colorless transparent oily liquid obtained by mixing, and then directly poured into a graduated vials for oral administration. When applying a measured quantity of oral fluid are selected and added to the water to form the emulsion oil-in-water for injection. Alternatively, you may direct injection of the emulsion, which spontaneously forms the base emulsion oil-in-water" upon contact with fluid body.

Example 18: the Pharmacokinetic experiment on rats after oral administration soft capsules with a self emulsifiable butylphthalide

Soft capsules with a self emulsifiable butylphthalide obtained in example 1 was used in the pharmacokinetic experiment after oral administration to rats. The results were compared with the results obtained for the commercially available soft capsules (the Content is a mixture of 100 mg butylphthalide and 300 mg of vegetable oil. Manufactured by NBP from SHIJIAZHUANG PHARM. GROUP). They are listed in table 4.

Table 4
Concentration butylphthalide in the blood plasma of rats at different time points after forced feeding
Time of sampling (hours)Concentration butylphthalide in blood (µg/ml)
Conventional soft capsuleSelf emulsifiable soft capsules
0,085,3213,62
0,176,7916,17
0,5of 8.060,87,029,3
110,15to 9.32
24,226,61
3or 4.31the 7.43
54,044,36
79,52,54
95,161,92
122,51,36

From table 4 one can see that for this offering self-emulsifying delivery system drug maximum concentration of drug achieved more quickly than conventional oil content. Their tmaxrepresents respectively 0.1 and 1.0 hour. In addition, the maximum concentration achieved by these soft capsules, is higher than that achieved by conventional soft capsules. For these soft capsules were observed less individual variation.

From vichar the led descriptions suggest, after getting into the gastrointestinal tract SEDDS first samoemulgirutisa drops in the emulsion and then spreads rapidly through the GI tract, thereby reducing the difference in the absorption of individuals that occur due to poor dispersion of the oil droplets, and reducing irritation caused by direct contact of the drug with the mucous membrane of the gastro-intestinal tract. In addition, the structure of droplets of the emulsion may change or be destroyed in the gastrointestinal tract. Most importantly, demonstrated promising clinical advantages through the use of self emulsifiable delivery system drug to lipid-soluble and less soluble oil drug - butylphthalide.

1. Offering self-emulsifying delivery system drug butylphthalide, characterized in that it contains by weight from 1 to 65% butylphthalide, from 10 to 65% of emulsifying agents and from 0 to 85% filler, based on the weight offering self-emulsifying delivery system drug butylphthalide, where the emulsifying agent is a mixture of polyoxyethylene castor oil and kaprilat/caprate the polyethyleneglycol-8 glycerin, where the ratio of the polyoxyethylene castor oil and kaprilat/caprate pole jingleball-8-glycerin is from 1:0.5 to 1:1.5 for the mass.

2. Offering self-emulsifying delivery system drug butylphthalide according to claim 1, containing by weight from 10 to 50% butylphthalide, from 15 to 60% of emulsifying agents and from 5 to 75% filler, based on the weight offering self-emulsifying delivery system drug butylphthalide.

3. Offering self-emulsifying delivery system drug butylphthalide according to claim 1 or 2, where butylphthalide selected from the group consisting of his racemic, levogyrate and programada isoforms.

4. Dosage form containing a self emulsifiable delivery system drug butylphthalide according to any one of claims 1 to 3.

5. Dosage form according to claim 4, where the dosage form is an oral liquid, while the dosage form optionally additionally contains water, solubilizers substance and/or flavoring.

6. Dosage form according to claim 4, where the dosage form is a soft capsule, while the dosage form optionally further comprises a vegetable oil, an antioxidant and/or flavoring.

7. Dosage form according to claim 6, in which the vegetable oil is selected from any one of the group consisting of sesame oil, corn oil, peanut oil, soybean oil, almond oil, oil of seeds of peach, cottonseed oil, podsolnuh the oil and olive oil, or a mixture of any two or more of these.

8. Dosage form according to claim 4, representing a solid dosage form selected from solid capsules, capsules, delayed release oral solid powders or granules, tablets, or tablets with delayed release, when this dosage form optionally further comprises loosening, binder, polymer reference substances and/or flavouring.

9. The method of obtaining the dosage form according to any one of claims 4 to 8, covering the complete melting and mixing emulsifying substances in a water bath of 20 to 60°C, then add butylphthalide with shaking and stirring, and adding a filler to get the dosage form, where the emulsifying agent is a mixture of polyoxyethylene castor oil and kaprilat/caprate the polyethyleneglycol-8 glycerin, where the ratio of the polyoxyethylene castor oil and kaprilat/caprate the polyethyleneglycol-8 glycerin is from 1:0.5 to 1:1.5 for the mass.



 

Same patents:

FIELD: medicine.

SUBSTANCE: invention refers to pharmaceutical set of cancerous disease treatment and prevention. The composition comprises cisdiammoniumdichlor-trans-dihydroxoplatinum (IV), in particular its salts, physically separated from the carrier selected from the group comprising tablet, capsule, coated pill, suppository, ointment, cream, solution for injection where the carrier is combined with cisdiammonium-dichlor-trans-dihydroxoplatinum (IV) immediately prior to use. The invention also refers to pharmaceutical composition obtained from the claimed set.

EFFECT: physical separation of active agent and carrier and their integration immediately before use enables to significantly increase antineoplastic activity of composition.

11 cl, 4 tbl

FIELD: medicine.

SUBSTANCE: invention is applied for treatment of purulent wounds and burns, pyoinflammatory dermatopathies, and for acceleration of healing and improvement of wound healing conditions. The composition possesses antibacterial and necrolytic action; it contains an active complex of bacteriolytic and proteolytic enzymes - Lisoamidase, and a base for soft formulation of the composition. The base contains a thermally stable perfluororganic compound emulsion with gas-transport properties and mixed hydrophilic substances specified as follows: proxanol-268, polyethylene oxides, propylene glycol, dimexide, hyaluronic acid or sodium hyaluronate, sorbite, glycerine, aerosil. Besides, the composition can contain at least one desired additive chosen from: anaesthetic (Chinoxycaine, Trimecaine, Pyromecaine, Lidocaine or mixed), a reparative process stimulator (methyluracil, acetamine, ethadene, calcium pantothenate, Solcoseryl or mixed) or mixed. The composition is made in the form of ointment or gel, rectal suppositories or capsules.

EFFECT: extended application, enhanced therapeutic activity and ease of use; lower consumption of the active substance; ensured anaesthetising effect; improved microcirculation in wound tissues, managed inflammatory processes, additional stimulation of reparative processes.

6 cl, 2 tbl, 19 ex

FIELD: medicine.

SUBSTANCE: invention concerns pharmaceutical technology and medicine and concerns a compound for capsules. The compound includes the β form of 2,4 dioxo-6-methyl-1,2,3,4-tetrahydropyrimidin as active substance. It also contains talc, calcium stearate and sucrose at a certain parity of components.

EFFECT: peroral intake of an agent; absence of irritating action on mucous coat of stomach.

3 ex

FIELD: medicine.

SUBSTANCE: invention concerns pharmaceutical technology and medicine and concerns a compound for capsules. An antimicrobial and interferon inducing agent includes a γ-modification of aminobenzenesulphamide as active substance. It also contains talc, calcium stearate and sucrose at a certain parity of components.

EFFECT: invention provides maximum therapeutic concentration of the preparation in blood.

3 ex

FIELD: medicine.

SUBSTANCE: medicinal preparation for diabetes treatment contains active pharmaceutical ingredients, obtained from root of rehmania (Radix Rehmanniae), root of astragalus (Radix Astragali), rhizomes of yam (Rhizoma Dioscoreae), root of kudzu hemp (Radix Puerariae Lobatae), root of snake gourd (Radix Trichosanthis), baculums with stigmas of corn (Stylus Zeae Maydis), fruits of schizandra (Fructus Schisandrae Sphenantherae) and Glibenclamidum (Glibenclamide), taken in a certain parity. Way of preparation of a medicinal preparation in the form of drop-pills. A way of preparation of a medicinal preparation in the form of pills. A way of preparation of a medicinal preparation in the form of capsules. A way of preparation of a medicinal preparation in the form of tablets. A way of preparation of a medicinal preparation in the form of granules. A way of preparation of a medicinal preparation in the form of soft capsules. A way of preparation of a medicinal preparation in the form of a powder.

EFFECT: efficiency for diabetes treatment.

14 cl, 3 tbl, 18 ex

FIELD: medicine.

SUBSTANCE: invention concerns a dispersion of crystals or granules of active substance in lipophilic filler where crystals or granules are covered for taste masking. The invention also concerns chewing or quickly dissolved soft gelatinous capsules filled with the specified dispersion, and also a way of manufacture of such forms. Use of considerable quantities of active substance which should be accepted at unitary introduction, and maintenance of satisfactory release of active substance in vivo is possible.

EFFECT: new dosed out forms are stable throughout all period of storage.

15 cl, 17 tbl, 5 ex

FIELD: medicine.

SUBSTANCE: present invention concerns area of medical products, in particular, to the capsule of a medicinal preparation made in the form of an elastic, soluble in a human body, monolithic body with a cavity for placing of a liquid medicinal preparation, having an inflow with a notch on an outer side, with the through aperture executed in it; the capsule is fixed on clothes. Such performance of the capsule excludes leak of a liquid medicinal preparation at an abruption from it, it is convenient for the patient as allows receiving a medicinal preparation in time.

EFFECT: exclusion of leak of a liquid medicinal preparation at an abruption from it, it is convenient for the patient as allows receiving a medicinal preparation in time.

1 dwg, 1 tbl, 5 ex

FIELD: medicine.

SUBSTANCE: invention refers to chemical-pharmaceutical industry and medicine, namely to oral gindarine medicine characterised as a tranquilizer. Said medicine contains gindarine hydrochloride as an active material and auxiliary components and represents a solid gelatinous capsule. Gindarine is included as a compound of the mass filling capsules as mixed powders of gindarine and auxiliary components or as a granulated material. As the auxiliary components, the medicine contains bulking agent either alone, or combined with a disintegrant or antifriction material or with their mixture. There is also provided method of production of specified oral medicine.

EFFECT: invention provides simplified technological process for making the gindarine medicine, reduction of defective goods, reduced production cost, higher bioavailability of gindarine in comparison with a tableted medical product.

4 cl, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention concerns medical products and concerns capsules for delivery of biologically active agent, containing: a water-soluble, washed away, blasted and-or bulking up cover; and b) the water filling composition including one or more active agents, the water which is in quantity from at least approximately 10% of masses/masses, to less than approximately 70% of masses/weights; and water-soluble derivative cyclodextrin, present at quantity of at least 30% of mass/mass, in recalculation on a total weight of water and derivative cyclodextrin in a filling composition where the quantity derivative cyclodextrin is enough for suppression of dissolution, washing out, destruction and-or a swelling of the cover, caused by water in a filling composition and where the capsule has a period of storage at least one week. Also the way of stabilisation of a capsule is opened.

EFFECT: creation of capsules with steady against dissolution, washing out, destruction and swelling covers.

51 cl, 11 dwg, 11 tbl, 10 ex

FIELD: medicine.

SUBSTANCE: pharmaceutical composition is intended for cancer treatment. As active ingredient composition contains suberoylanilide-hydroxamic acid (SAHA) or its pharmaceutically acceptable salt or hydrate. Invention also relates to method of obtaining crystalline active ingredient SAHA.

EFFECT: definite profile of SAHA particles distribution according to their size, which in its turn results in improved profile of solubility in vitro and optimal SAHA bioavailability.

27 cl, 16 dwg, 22 tbl, 17 ex

FIELD: medicine.

SUBSTANCE: method of obtaining tablets containing crystalline-form-free alprazolam, includes at preliminary stage of granulation operation obtaining alprazolam solution in pharmacologically acceptable solvent together with crystallisation-inhibiting agent, formed by mixture of binding substance and from 20 to 60% wt of total amount of lubricating substance, impregnation with obtained solution of mixture of diluent and 25% reticular carboxymethylcellulose as disintegrating agent until homogeneous granulated mass is obtained and grinding of obtained granulated mass, preliminarily dried, until grinded granulometrically homogeneous mass is obtained. At the second stage of granulation operation, 100% of remaining lubricating agent and remaining reticular carboxymethylcellulose and aromatising additives are added to dried and grinded mass, obtained at preliminary stage of granulation operation; aromatised mass is finally mixed and pressed. Non-crystalline state of alprazolam improves its solvability and bioaccessibility.

EFFECT: alprazolam tablets have smaller size than traditional tablets, and disintegration time less than 1 minute, preferably, less than 30 seconds.

11 cl, 7 dwg, 3 tbl, 3 ex

FIELD: medicine.

SUBSTANCE: invention refers to pharmaceutical set of cancerous disease treatment and prevention. The composition comprises cisdiammoniumdichlor-trans-dihydroxoplatinum (IV), in particular its salts, physically separated from the carrier selected from the group comprising tablet, capsule, coated pill, suppository, ointment, cream, solution for injection where the carrier is combined with cisdiammonium-dichlor-trans-dihydroxoplatinum (IV) immediately prior to use. The invention also refers to pharmaceutical composition obtained from the claimed set.

EFFECT: physical separation of active agent and carrier and their integration immediately before use enables to significantly increase antineoplastic activity of composition.

11 cl, 4 tbl

FIELD: medicine.

SUBSTANCE: invention refers to medicine, specifically to an antidiabetic composition. Said composition for diabetes treatment contains pioglitazone hydrochloride as an active substance and lactose, microcrystalline cellulose, oxypropylcellulose, sodium croscarmellose, aerosil and stearic acid salt as additives. Preferentially, the composition is tableted; each tablet contains the active substance in amount 15 mg, 30 mg or 45 mg (per pioglitazone).

EFFECT: offered composition is resolved quickly (1-2 minutes and less), easily release the active component (95-100% of pioglitazone passes into a dissolution medium 30 minutes later), is characterised by high breaking strength and abrasion resistance, storage stability of quality level that ensures effective life for 2 years and more.

6 cl, 1 tbl, 4 ex

FIELD: medicine.

SUBSTANCE: invention concerns medicine, namely to the agents possessing antituberculous action and used in phthisiology. The tablet contains 1-isonicotinyl-2-glucosylhydrazone dihydrate (isoglucosyl), hydroxypropylmethylcellulose or methylcellulose and calcium stearate. The tablet can be covered by a cover. The invention provides high therapeutic efficiency and hypotoxicity of the new agent in comparison with known antituberculous forms of Isoniaside and rifampicin.

EFFECT: provision of high therapeutic efficiency and hypotoxicity of the new agent in comparison with known antituberculous forms of Isoniaside and rifampicin.

2 cl, 1 tbl

Medicinal agent // 2363463

FIELD: medicine.

SUBSTANCE: invention relates to medicine and pharmaceutical industry, and more specifically to making tableted dosage form with prophylactic effect for arresting primed reaction to radiation and early transient incapacity. The agent contains ondansetron, methacin and caffeine in weight ratio ondansetron:methacin:caffeine 4:1:20-300.

EFFECT: reduced adverse reaction, more specifically vomiting, diarrhea and reduction of physical activity.

5 cl, 11 tbl

FIELD: medicine.

SUBSTANCE: present invention relates to pharmaceutics and a tablet with high drug content, which contains an active component in form of a formula (I) compound or its pharmaceutically acceptable salt in amount of approximately 30-80 wt % of active component, in total mass of the tablet and at least one binding substance, which contains microcrystalline cellulose or hydroxypropylmethicellulose.

EFFECT: design of a tablet with high drug content.

16 cl, 1 dwg, 3 ex

FIELD: medicine.

SUBSTANCE: medicinal preparation for diabetes treatment contains active pharmaceutical ingredients, obtained from root of rehmania (Radix Rehmanniae), root of astragalus (Radix Astragali), rhizomes of yam (Rhizoma Dioscoreae), root of kudzu hemp (Radix Puerariae Lobatae), root of snake gourd (Radix Trichosanthis), baculums with stigmas of corn (Stylus Zeae Maydis), fruits of schizandra (Fructus Schisandrae Sphenantherae) and Glibenclamidum (Glibenclamide), taken in a certain parity. Way of preparation of a medicinal preparation in the form of drop-pills. A way of preparation of a medicinal preparation in the form of pills. A way of preparation of a medicinal preparation in the form of capsules. A way of preparation of a medicinal preparation in the form of tablets. A way of preparation of a medicinal preparation in the form of granules. A way of preparation of a medicinal preparation in the form of soft capsules. A way of preparation of a medicinal preparation in the form of a powder.

EFFECT: efficiency for diabetes treatment.

14 cl, 3 tbl, 18 ex

FIELD: medicine.

SUBSTANCE: invention reveals a composition for reception of the pressed solid dosed out form which represents a free-fluid pressed simethicon admixture, an adsorbent and the unessential active agent where the weight parity of simethicon and an adsorbent makes at least 1:2.22. The invention also opens the solid dosed out forms received from a free-fluid pressed simethicon admixture, an adsorbent and the unessential active agent where the weight parity of simethicon and an adsorbent makes at least 1:2.22.

EFFECT: solid dosed out form contains larger simethicon percentage by weight, having same size as before, or contains the same simethicon percentage by weight in smaller volume.

27 cl, 11 ex

FIELD: medicine; pharmaceutics.

SUBSTANCE: invention concerns a way of reception of the pharmaceutical composition containing fenophibrate as active substance or one of its derivatives, if needed in association with the second active substance, in the form of tablets, differing that it includes a stage of compaction of active substance and excipients using dry granulation.

EFFECT: simplification of a way of reception of a tablet, with conservation of high bioavailability of active substance.

23 cl, 4 ex, 20 tbl

FIELD: medicine.

SUBSTANCE: invention concerns a tablet containing fluvastatin with sodium carboxymethylcellulose of calcium in the form of raising agent. The fluvastatin tablet is characterised by time of disintegration from 10 to 30 minutes and good bioavailability equivalent to bioavailability of serially produced capsules, containing fluvastatin. Manufacturing of tablets does peroral application of fluvastatin economically more favourable and more convenient for patients.

EFFECT: rising of profitability and convenience of peroral fluvastatin application to patients.

12 cl, 7 dwg, 6 tbl, 2 ex

FIELD: medicine.

SUBSTANCE: invention relates to novel emulsion of "oil in water" type intended for parenteral introduction. Emulsion contains as active ingredient badly soluble in water compound with anti-tumor activity of taxans class, for example paclitaxel or docetaxel in concentration from 1 to 30 mg in 1 ml of emulsion. Emulsion also contains lecithin, effective quantity of antioxidant, stabiliser of emulsion, dimethylsulphoxide as co-solvent of active ingredient and lactide or glycolide co-polymer as active ingredient stabiliser. Emulsion contains particles with size less than 100 nm in quantity not less than 80%. Emulsion by invention is stable when diluted with infusion solutions.

EFFECT: invention removes defects, connected with presence in applied in therapy of tumor diseases compositions of co-solvents, which have toxic effect on human organism, as well as with instability of known emulsions in dilution with infusion solvents.

29 cl, 6 dwg, 1 tbl, 7 ex

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