CN114073689B - Extraction-preventing pharmaceutical composition and preparation thereof - Google Patents

Extraction-preventing pharmaceutical composition and preparation thereof Download PDF

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Publication number
CN114073689B
CN114073689B CN202010796527.5A CN202010796527A CN114073689B CN 114073689 B CN114073689 B CN 114073689B CN 202010796527 A CN202010796527 A CN 202010796527A CN 114073689 B CN114073689 B CN 114073689B
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extraction
pharmaceutical composition
mass ratio
pharmaceutical
ephedrine
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CN114073689A (en
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蒋志君
曹青日
陈幸幸
张茂风
秦飞
陆小娟
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JIANGSU CHANGTAI PHARMACEUTICAL CO Ltd
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Jiang Su Pharmamaxcorp Co ltd
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    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
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    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
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    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
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Abstract

The invention provides an extraction-preventing pharmaceutical composition, which comprises an active ingredient and pharmaceutical auxiliary materials, wherein the active ingredient comprises ephedrine substances or pharmaceutically acceptable salts thereof, and the pharmaceutical auxiliary materials comprise high-molecular polymer framework materials and purification-influencing additives. The invention also provides a pharmaceutical preparation, which comprises the pharmaceutical composition provided by the invention. The extraction-preventing pharmaceutical composition and the pharmaceutical preparation can generate strong effects of emulsification, swelling, gelation and the like in the extraction process, and the purity and the recovery rate of the extracted extract are low, so that the aims of preventing toxin production and drug abuse can be effectively achieved, the effect is obviously superior to that of similar products sold in the market, and the raw materials used by the extraction-preventing pharmaceutical composition are low in cost and easy to obtain, and the preparation method is simple and convenient and has economic and social values.

Description

Extraction-preventing pharmaceutical composition and preparation thereof
Technical Field
The invention relates to the field of medicines, in particular to an extraction-preventing pharmaceutical composition and a pharmaceutical preparation containing the pharmaceutical composition.
Background
The easy-to-prepare chemicals refer to precursors, raw materials, chemical auxiliaries and the like which are regulated by national regulations and can be used for manufacturing drugs. Ephedrine is a kind of easily-made chemicals specified in China, and mainly comprises pseudoephedrine hydrochloride, pseudoephedrine sulfate, ephedrine hydrochloride, ephedrine sulfate, phenylpropanolamine hydrochloride and the like.
Pseudoephedrine hydrochloride is one of the most commonly used sympathomimetic agonists and is widely used for the treatment of respiratory diseases, cold resistance, etc. Pseudoephedrine hydrochloride can also be used as a raw material for synthesizing drugs, and methamphetamine (commonly known as methamphetamine) is obtained through reaction. Many formulators obtain purer pseudoephedrine by simple extraction and use it in the manufacture of methamphetamine by purchasing commercial products such as new kangtak, melagatran and the like containing pseudoephedrine hydrochloride. In the extraction of pseudoephedrine, an important step is extraction with a water-insoluble organic solvent, followed by separation of the organic layer.
In order to prevent the illegal abuse of pseudoephedrine or other similar drugs, several drug composition design ideas are reported at present, and summarized as follows: (1) tamper-proof: before illegal application, the medicine is firstly crushed, and the crushing, crushing or breaking strength of the preparation is increased, so that a toxicant cannot be crushed by a conventional tool, and the probability of illegal application is further reduced. (2) extraction prevention: by selecting proper auxiliary materials, the extraction difficulty is increased, the purification rate is reduced, or the emulsification degree during extraction is increased, so that the extraction process is difficult to smoothly proceed, and the extraction process can be effectively inhibited. (3) anti-transformation: adding proper additive to block the chemical reaction of pseudoephedrine to ice toxin.
Therefore, the current research mainly comprises the steps of increasing the breaking strength of the preparation or adding interference components to interfere the processes of extraction, conversion and the like of pseudoephedrine or other similar medicaments, so that the toxicity difficulty of a toxicity producer is increased. Although some related techniques have been reported, the effects achieved are still quite limited.
Disclosure of Invention
In order to overcome the defects in the prior art, the invention aims to provide an extraction-preventing pharmaceutical composition which can effectively prevent ephedrine active ingredients from being extracted, thereby effectively achieving the purpose of preventing drugs from being abused.
It is another object of the present invention to provide a pharmaceutical formulation.
The extraction-preventing pharmaceutical composition provided by the invention comprises an active ingredient and pharmaceutical auxiliary materials, wherein the active ingredient comprises ephedrine substances or pharmaceutically acceptable salts thereof, and the pharmaceutical auxiliary materials comprise high-molecular polymer framework materials and purification-influencing additives; wherein the high molecular polymer framework material comprises polyoxyethylene, povidone and cellulose derivatives, and the purification influencing additive consists of cholesterol and one or more of the following surfactants: tween 80, lecithin, poloxamer, sodium lauryl sulfate, stearic acid, oleic acid, lauric acid, sodium dioctyl succinate sulfonate, sodium glycocholate, glyceryl monostearate or zel.
The extraction-preventing pharmaceutical composition provided by the invention can generate strong effects of emulsification, swelling, gelation and the like in the extraction process of ephedrine substances by adding the high molecular polymer framework material and affecting the purification additive, so that the active ingredients are difficult to separate, the extraction time is obviously prolonged, serious extraction barriers are manufactured, and even if the extract is barely separated, the purity of the active ingredients is lower, the recovery rate is lower, so that the extraction cost is greatly increased, thereby effectively achieving the purposes of preventing toxicity and drug abuse.
In the anti-extraction pharmaceutical composition provided by the invention, the mass ratio of the ephedrine substance or pharmaceutically acceptable salt thereof, the high polymer framework material and the purification influencing additive can be 1:1 to 15:0.01 to 5. In some preferred embodiments, the mass ratio of the ephedrine class substance or pharmaceutically acceptable salt thereof, the high molecular polymer matrix material, and the purification-affecting additive may be 1:1 to 8: 0.02-3. Specifically, when the ephedrine compound or the pharmaceutically acceptable salt thereof in the pharmaceutical composition is 1 part by weight, the amount of the high molecular polymer skeleton material includes, but is not limited to, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, etc. parts by weight or any part by weight interval combination, and the amount of the purification affecting additive includes, but is not limited to, 0.01, 0.05, 0.1, 0.2, 0.5, 0.8, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, etc. parts by weight or any part by weight interval combination.
In the anti-extraction pharmaceutical composition provided by the invention, the surfactant is further preferably selected from one or more of tween 80, lecithin and poloxamer. In some preferred embodiments, the purification-affecting additive consists of cholesterol and tween 80, or cholesterol and lecithin.
In some more preferred embodiments, the purification-affecting additive consists of cholesterol and tween 80, the mass ratio of cholesterol to tween 80 may be from 0.1 to 10:1. in some most preferred embodiments, the mass ratio of the cholesterol to the tween 80 may be 0.2 to 5:1, including but not limited to 0.2: 1. 0.5:1. 1: 1. 1.5: 1.2: 1. 2.5: 1. 3: 1. 3.5: 1. 4: 1. 4.5: 1.5:1 equal mass ratio or any combination of mass ratio intervals.
In other more preferred embodiments, the purification-affecting additive consists of cholesterol and lecithin, the mass ratio of cholesterol to lecithin may be 0.1 to 10:1. in some most preferred embodiments, the mass ratio of the cholesterol to the lecithin may be 0.2 to 5:1, including but not limited to 0.2: 1. 0.5:1. 1: 1. 1.5: 1.2: 1. 2.5: 1. 3: 1. 3.5: 1. 4: 1. 4.5: 1.5:1 equal mass ratio or any combination of mass ratio intervals.
In the anti-extraction pharmaceutical composition provided by the invention, in the high polymer framework material, the mass ratio of the polyoxyethylene, the cellulose derivative and the povidone can be 1-10: 1-20: 1. in some preferred embodiments, the mass ratio of the polyoxyethylene, the cellulose derivative, and the povidone may be 1.5 to 6:1 to 10:1. specifically, when the povidone in the high molecular polymer skeleton material is 1 part by weight, the amount of the polyoxyethylene includes, but is not limited to, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 7, 8, 9, 10, etc., or any part by weight of the interval combination, and the amount of the cellulose derivative includes, but is not limited to, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, etc., or any part by weight of the interval combination.
In some preferred embodiments, the cellulose derivative may be selected from one or more of microcrystalline cellulose, methylcellulose, hydroxypropyl cellulose, hypromellose. In some more preferred embodiments, the cellulose derivative may be selected from hydroxypropyl cellulose and/or hypromellose.
In the anti-extraction pharmaceutical composition provided by the invention, the pharmaceutical auxiliary materials can also comprise auxiliary agents, and the mass ratio of the auxiliary agents to the ephedrine substance or the pharmaceutically acceptable salt thereof can be 0.01-1.5: 1, including but not limited to 0.01: 1. 0.02: 1. 0.05: 1. 0.1: 1. 0.2: 1. 0.3: 1. 0.4: 1. 0.5:1. 0.6: 1. 0.7: 1. 0.8: 1. 0.9: 1. 1: 1. 1.2: 1. 1.5:1 equal mass ratio or any combination of mass ratio intervals. In some preferred embodiments, the mass ratio of the auxiliary agent to the ephedrine class substance or pharmaceutically acceptable salt thereof may be 0.02 to 0.5:1.
in some preferred embodiments, the auxiliary agent may be selected from ferric citrate and/or vitamin E. In some more preferred embodiments, the auxiliary agent consists of ferric citrate and vitamin E, and the mass ratio may be 1: 1-10, including but not limited to 1: 1. 1: 2. 1: 3. 1: 4. 1: 5. 1: 6. 1: 7. 1: 8. 1: 9. 1:10 equal mass ratio or any combination of mass ratio intervals. In some further preferred embodiments, the mass ratio of the ferric citrate to the vitamin may be 1:2 to 5.
In the anti-extraction pharmaceutical composition provided by the invention, the ephedrine substance can be any kind or any derivative thereof, preferably one or more selected from ephedrine, pseudoephedrine, racemic ephedrine, norephedrine, methyl ephedrine and ephedrine extract powder, and the pharmaceutically acceptable salt can be any salt, such as inorganic acid salt or organic acid salt, preferably one or more selected from hydrochloride, sulfate, fumarate and maleate.
The anti-extraction pharmaceutical composition provided by the invention can contain other types of active ingredients besides ephedrine substances or pharmaceutically acceptable salts thereof, especially active ingredients in medicaments for treating respiratory diseases, cold resistance and the like, including but not limited to one or more of the following ingredients: acetaminophen, chlorpheniramine maleate, chloromatamine fumarate, azatadine maleate, chloramphenicol maleate, dextromethorphan hydrobromide, diphenhydramine hydrochloride, naproxen sodium, atorvastatin, loratadine hydrochloride, thiazine hydrochloride, ibuprofen, cetirizine, fexofenadine hydrochloride, triprolidine hydrochloride, and guaifenesin.
The invention also provides a pharmaceutical preparation, which comprises the anti-extraction pharmaceutical composition according to any one of the technical schemes.
The pharmaceutical formulation provided by the present invention may be used in amounts selected by one skilled in the art depending on factors such as the different dosage forms, the different applications, etc. In some preferred embodiments, the ephedrine or pharmaceutically acceptable salt thereof may be 3-30% by mass of the pharmaceutical formulation; in some more preferred embodiments, the ephedrine or pharmaceutically acceptable salt thereof may be 10 to 30% by mass of the pharmaceutical preparation.
The pharmaceutical preparation provided by the invention can contain any pharmaceutically acceptable carrier besides the anti-extraction pharmaceutical composition, including but not limited to filling agents, adhesives, disintegrants, coating agents, salts, lubricants and the like, and the types of the carriers can also be any pharmaceutically acceptable type, for example, the filling agents comprise one or more of lactose, sucrose, xylitol, sorbitol, calcium sulfate, mannitol, dextrin, starch, diatomite and kaolin; the binder includes, but is not limited to, one or more of pregelatinized starch, water-soluble resin; the disintegrants include, but are not limited to, one or more of crospovidone, low-substituted hydroxypropyl cellulose, croscarmellose sodium, and sodium carboxymethyl starch; the coating agent comprises one or more of acrylic resin, cellulose acetate phthalate, polyvinyl alcohol phthalate and cellulose acetate trimellitate; the salts include, but are not limited to, one or more of ferrous sulfate, ferrous chloride, ferrous nitrate, ferrous phosphate, ferrous gluconate, zinc sulfate, zinc chloride, zinc nitrate, zinc phosphate, zinc gluconate; the lubricant comprises one or more of magnesium stearate, micro silica gel, talcum powder, calcium stearate, polyethylene glycol 6000 and methyl silicone oil.
The pharmaceutical preparation provided by the invention can be prepared into any dosage form according to different applications. In some preferred embodiments, the pharmaceutical formulation may be a solid formulation including, but not limited to, tablets, capsules, granules, powders, drop pills, and the like.
The pharmaceutical formulations provided by the present invention may be prepared by selecting processes and equipment well known in the art according to different dosage forms.
The extraction-preventing pharmaceutical composition and the pharmaceutical preparation provided by the invention have the following advantages:
the pharmaceutical composition and the pharmaceutical preparation can generate strong effects of emulsification, swelling, gelation and the like in the extraction process, so that ephedrine active ingredients are difficult to separate, and even if the extract is separated, the purity of the active ingredients is lower or the recovery rate is lower, thereby effectively achieving the purposes of preventing toxin and preventing drug abuse, and the effect is obviously better than that of similar products sold in the market.
The raw materials used for the anti-extraction pharmaceutical composition and the pharmaceutical preparation are cheap and easy to obtain, the preparation method is simple and convenient, and the anti-extraction pharmaceutical composition and the pharmaceutical preparation are suitable for common ephedrine pharmaceutical dosage forms and have economic and social values.
Detailed Description
The technical scheme of the invention is further described in detail below with reference to specific embodiments.
The raw materials and equipment used in the examples are shown in tables 1 and 2, respectively, and other raw materials and equipment are commercially available products unless otherwise specified.
TABLE 1 raw materials
Raw material name Model number Manufacturer' s
Pseudoephedrine hydrochloride NA ZHEJIANG APELOA KANGYU PHARMACEUTICAL Co.,Ltd.
Cholesterol NA Zhengzhou Huafeng food technology Co., ltd
Tween 80 NA Sichuan Jinshan Pharmaceutical Co.,Ltd.
Lecithin NA French Biotechnology Co., ltd
Polyoxyethylene (Polyox) WSR 301NF Colorcon
Hydroxypropyl cellulose (Klucel) HXF Aqualon
Hydroxypropyl methylcellulose (HPMC) K100M premium Dow chemistry
Microcrystalline cellulose PH101 FMC Biopolymer
Povidone K30 BASF Corp.
Croscarmellose sodium NA Germany JRS Co
Vitamin E NA Jiaxing Tianhe Chengsheng Co., ltd
Ferric citrate NA Baoling Fujin Biotechnology Co.,Ltd.
Table 2 apparatus
Device name Model number Manufacturer' s
Granulating machine G6 Shenzhen City Xinyite Co., ltd
FZ series crushing and granulating machine 150 type Jiangyin city Lingling mechanical manufacturing Limited company
Heated air circulation oven DHG3132A Shanghai precision laboratory Equipment Co.Ltd
Three-dimensional motion mixer HD-15 CHANGZHOU PENGDUO DRYING EQUIPMENT Co.,Ltd.
Tablet press ZP-12A BEIJING GYLONGLI SCI.& TECH. Co.,Ltd.
Rotary evaporator RE-52AA SHANGHAI TOO THE CHINA INSTRUMENT AND EQUIPMENT Co.,Ltd.
High performance liquid chromatograph e2695-2489 Waters
The percentages used in the examples of the present invention are mass percentages unless otherwise indicated.
Example 1
The formulation of the composition of example 1 (composition 1) is as follows:
the composition samples were prepared manually for extraction experiments and content determination. The materials were added in 30 times for preparation as indicated by the above prescription.
The preparation process is as follows:
1) Placing solid material pseudoephedrine hydrochloride, cholesterol, hydroxypropyl cellulose, vitamin E, ferric citrate and povidone in a small tray for manual mixing to obtain a mixture.
2) Preparing Tween 80 into 7wt% concentration water solution, spraying half volume of Tween 80 solution into the mixture obtained in the step 1), and slightly stirring; then adding polyoxyethylene for secondary mixing, spraying the rest half of Tween 80 solution to obtain soft material, and drying the soft material in a hot air circulation oven (60 ℃ for 8 h).
3) Taking a dried soft material, grinding and crushing for later use.
Example 2
The formulation of the composition of example 2 (composition 2) is as follows:
the preparation procedure is as in example 1.
Example 3
Example 3 the composition (composition 3) was formulated as follows:
the preparation procedure is as in example 1.
Example 4
Example 4 composition (composition 4) was formulated as follows:
the preparation procedure is as in example 1.
Example 5
Example 5 the composition (composition 5) was formulated as follows:
the preparation procedure is as in example 1.
Example 6
Example 6 the composition (composition 6) was formulated as follows:
the preparation procedure is as in example 1.
Example 7
Example 7 the composition (composition 7) was formulated as follows:
the preparation procedure is as in example 1.
Example 8
Example 8 composition (composition 8) was formulated as follows:
the preparation procedure is as in example 1.
Example 9
Example 9 composition (composition 9) was formulated as follows:
the preparation procedure is as in example 1.
Example 10
Example 10 the composition (composition 10) was formulated as follows:
the preparation procedure is as in example 1.
Example 11
The formulation of the composition of example 11 (composition 11) is as follows:
the preparation procedure is as in example 1.
Example 12
The formulation of the composition of example 12 (composition 12) is as follows:
the preparation procedure is as in example 1.
Example 13
The formulation of the composition of example 13 (composition 13) is as follows:
the preparation procedure is as in example 1.
Example 14
Example 14 the composition (composition 14) was formulated as follows:
the preparation procedure is as in example 1.
Example 15
The recipe for example 15 is as follows:
note that: the above table is the unit formulation recipe.
Formulation development was performed as prescribed in example 15.
1. Tablet:
1) Mixing: taking pseudoephedrine hydrochloride, chlorpheniramine maleate, cholesterol, microcrystalline cellulose, hydroxypropyl cellulose, povidone, vitamin E and croscarmellose sodium according to 1000 times of the prescription dosage of the unit preparation, and sieving. Adding the materials into a high-speed mixing granulator for mixing, mixing parameters, and stirring: 5r/s, granulating blade rotation speed: 7/s, running for 3min.
2) Preparing soft materials and wet particles: tween 80 was formulated as a 10% aqueous solution, spray added to the above mixture, wet mixed granulation at high speed. Granulator parameters: stirring: 6r/s, running for 2min; granulating knife: 8/s, and running for 1min.
3) Wet finishing and drying: finishing parameters: 2.0mm screen mesh sieving and granulating, motor rotation speed: 400rpm. Drying parameters: the soft material was dried at 60℃for 3h (moisture 1.65%).
4) And (3) dry finishing: finishing parameters: 2.0mm screen mesh sieving and granulating, motor rotation speed: 400rpm. (yield of dry particles 87%).
5) Total mixing: adding the dry particles, polyoxyethylene and talcum powder into an HD three-dimensional motion mixer, carrying out total mixing at the rotating speed of 10r/min, and mixing for 3min.
6) Tabletting: and (3) a mold: 14 x 6.3 punches, capsule punches. Sheet weight: 300mg, hardness: 120N.
2. Granule and capsule:
the process proceeds to step 4) following the above-described tablet procedure, and the dry granulation, polyoxyethylene, are then added to the HD three-dimensional motion mixer and mixed. The rotation speed is 10r/min, and the mixing is carried out for 3min.
And subpackaging the obtained granules to obtain granules.
And filling the obtained granules into capsules to obtain capsules.
Test example 1 extraction solvent screening experiment
According to the polarity sequence of the organic solvents, water, acetonitrile, ethanol, ethyl acetate, diethyl ether, dichloromethane, chloroform, carbon tetrachloride, carbon disulfide, cyclohexane, hexane and petroleum ether are selected. The extraction solvent used in this experiment is well representative.
Extraction experiment a) 2.0g of sample was weighed, ground, added to a 100mL beaker, added with 40mL of purified water, stirred for 10min, added with 3mL of 2M NaOH solution, transferred to a separatory funnel, added with 40mL of n-hexane, shaken vigorously, and waited for delamination.
Extraction experiment B) 2.0g of sample was weighed, ground, added to a 100mL beaker, added with 40mL of purified water, stirred for 10min, added with 3mL of 2M NaOH solution, transferred to a separatory funnel, added with 40mL of dichloromethane, shaken vigorously, and waited for delamination.
Extraction experiment C) weighing 2.0g of sample, grinding, adding into a 100mL beaker, adding 30mL of methanol, stirring for 10min, filtering insoluble substances, adding 20mL of methanol to wash a filter cake, concentrating and drying the filtrate to obtain the sample.
Extraction experiment D) 2.0g of sample was weighed, ground, added to a 100mL beaker, added with 40mL of purified water, stirred for 10min, added with 3mL of 2M NaOH solution, transferred to a separating funnel, added with 30mL of diethyl ether, vigorously shaken, and waited for delamination.
TABLE 3 extraction solvent screening test results
Note that: the 'emulsification' in the table actually refers to the comprehensive effects of emulsification, material swelling, material gelation and the like, and the strength of the emulsion is determined by the separation time of the water layer and the organic layer.
The results show that when extracted with water-immiscible organic solvents (e.g., n-hexane, methylene chloride, diethyl ether), composition 1 of example 1 of the present invention produced a strong emulsifying effect during the extraction (e.g., experiment A, B, D in Table 3), and that the organic and aqueous phases were difficult to separate in a short period of time. When most common toxicants face the first re-checkpoint, the extraction behavior has to be abandoned due to no expert knowledge, so that the effect of inhibiting the extraction behavior is achieved. In addition, when extracted with a water-miscible organic solvent (e.g., methanol), composition 1 of example 1 of the present invention swells and gels during the suction filtration process, which tends to plug the suction filtration medium (e.g., experiment No. C in table 3). In summary, it is difficult to extract the active ingredient simply and rapidly when the composition of the present invention is extracted using organic solvents of various polarities.
Test example 2 evaluation experiment of extraction Effect
A) Referring to the extraction experiment a of test example 1, an extraction sample was prepared by extracting with n-hexane, allowing the extract to stand for a long period of time to separate an organic layer, concentrating under reduced pressure, and drying.
B) Referring to the extraction experiment B of test example 1, an extraction sample was prepared by extracting with methylene chloride, allowing the extract to stand for a long time to separate the layers, concentrating the separated organic layer under reduced pressure, and drying.
C) Referring to test example 1, an extraction experiment C was performed by methanol extraction to prepare an extraction sample.
The samples extracted from the above experiments were weighed, the purity of the samples was checked by High Performance Liquid Chromatography (HPLC), and the ephedrine recovery rate was calculated based on the purity and the weight of the extract, and the results are shown in table 4.
HPLC assay was analyzed as follows:
1. apparatus and device: waters spherisorb, SCX, 4.6X105 mm,5- μm particle size or performance equivalent high performance liquid chromatograph, with liquid pump, UV or PDA detector and controllable Wen Zhuwen tank, 0.45- μm aqueous filter.
2. Mobile phase: 600mL of ammonium acetate buffer salt solution and 400mL of acetonitrile are mixed uniformly and degassed. Wherein, the preparation of ammonium acetate buffer salt solution (20 mM): 3.08g to 2000mL of ammonium acetate was taken, 1.0mL of triethylamine was added thereto, pH was adjusted to 5.0.+ -. 0.05 with acetic acid, stirred well and filtered through a 0.45-. Mu.m aqueous filter.
3. Chromatographic conditions:
flow rate 2.0mL/min
Wavelength of 260nm
Sample injection amount 20μl
Autoinjector temperature/sample cell temperature Room temperature
Column temperature 30℃
Run time ～15min
TABLE 4 summary of the extraction results
Note that: recovery of pseudoephedrine free base, b recovery of pseudoephedrine hydrochloride, N indicates that the index was not applicable, x indicates that insoluble floc was included in the calculation at the time of extraction separation. The 'emulsification' actually refers to the combined effects of emulsification, material swelling and material gelation, and the strength of the emulsion is determined by the separation time of the water layer and the organic layer. The extraction solvent added was varied in volume according to the amount of the added material, and the ratio was referred to the extraction experimental procedure in test example 1.
Table 5 extraction prevention effect score
Note 1: the emulsification score (E) is set to 0-0.4, the larger the value is, the stronger the emulsification is, and N represents that the index is not applicable; the 'emulsification' in the table actually refers to the comprehensive effects of emulsification, material swelling, material gelation and the like, and the strength of the emulsion is determined by the separation time of the water layer and the organic layer.
And (2) injection: A. multifactor integrated value for experiment no: x= (p+r)/2+ (0.4-E), experimental multifactor integrated value No. C: x= (p+r)/2; single solvent extraction prevention composite score: s=1/x×30; multi-solvent extraction prevention composite score: m is M n ＝0.2×S nA +0.5×S nB +0.3×S nC . The higher the extraction prevention comprehensive score value is, the better the extraction prevention effect is.
And (3) injection: new Kang Taike refers to a slow release capsule of pseudoephedrine hydrochloride of New Kangtaike compound produced by Midsikovia, and the extraction experiment is carried out by taking the particles in the capsule. Each granule contained 90 mg of pseudoephedrine hydrochloride and 4 mg of chlorpheniramine maleate. The auxiliary materials comprise: starch, sucrose, hypromellose, ethylcellulose, opal pink dry spray, opal yellow dry spray.
The results in tables 3-5 show that the pharmaceutical composition of the present invention has multiple extraction preventing effects. The method is specifically characterized in two aspects: the multi-solvent extraction-preventing agent has a double-checkpoint function and a multi-solvent extraction-preventing effect. Regarding the double-checkpoint function, checkpoint one means that the extraction process produces strong emulsification, swelling, gelation, etc., resulting in difficulty in separation, so that a large number of toxicants have to discard the extraction behavior (the result of table 3); the second point is that even though the drug producer separates the extract, the lower purity and recovery rate are not beneficial to the subsequent transformation experiments, so that the drug production cost is greatly increased, and the drug production plan may be abandoned. According to the extraction results (tables 4 and 5), the purity and recovery rate of the extract are mostly lower than 50%, the extract has better extraction prevention effect, and each effect is better than that of the same kind of drug Xinkangtai on the market.
It is noted that the compositions provided herein achieve low purity, or low recovery, or easy emulsification/swelling/gelation in a variety of solvent extractions. Because the extraction results of the same prescription in different solvents have different, such as the comprehensive effect of emulsification/swelling/gelation, purity and recovery rate, in order to facilitate comprehensive investigation of the multi-solvent extraction prevention effect of a certain prescription and determine a preferable prescription, the invention also provides a set of evaluation models, and factors such as the emulsification/swelling/gelation effect, purity, recovery rate, different solvents and the like are introduced into a scoring system, and the higher the comprehensive value of the extraction prevention score, the better the extraction prevention effect. Compared with the New Kangtai Ke, the embodiment composition provided by the invention also has remarkable advantages in multi-solvent extraction prevention comprehensive evaluation.
The results show that the composition provided by the invention has multiple extraction prevention functions, so that the extraction prevention purpose can be effectively achieved.
Test example 3 experiments on analysis of key ingredients leading to effects of emulsification, swelling, gelation, etc
50mg of the materials (specific ingredients are shown in Table 6) were weighed separately, placed in a small centrifuge tube, 1mL of each of water and methylene chloride was added, shaken for 10 seconds, left stand, and emulsification and delamination were observed.
The results are shown below:
"-": after extraction, standing for 5 minutes, the mixture can be obviously layered without emulsifying phenomenon;
"+": after extraction, standing for 15 minutes, wherein the volume of the emulsion layer (comprising swellings and gels) is lower than 20% of the total volume, and completely layering within 5 hours;
"++": after extraction, standing for 15 minutes, wherein the volume of the emulsion layer (comprising swellings and gels) is less than 30% of the total volume, and standing for 5 hours for about 90% of the emulsion layer to delaminate;
"+++": after extraction, standing for 15 minutes, wherein the volume of the emulsion layer (comprising swellings and gels) is higher than 30% of the total volume, and standing for 10 hours for about 90% layering;
"++++": after extraction, the emulsion layer (including swellings and gels) had a volume of greater than 65% of the total volume and was not delaminated after 10 hours of standing for 15 minutes.
TABLE 6 analysis of key ingredients leading to effects of emulsification, swelling, gelation, etc
The results in Table 6 show that the main materials in the pharmaceutical composition of the invention have different degrees of emulsifying, swelling or gelling properties, especially cholesterol and Tween 80, which are the basis of the strong emulsifying capacity of the composition during extraction. In addition, the combination of materials comprising cholesterol and tween 80 achieved a stronger emulsifying, swelling and gelling capacity than the single material. Therefore, the pharmaceutical composition provided by the invention can generate a strong 'blocking' effect in the extraction process, so that the aims of preventing extraction, toxin control and abuse can be effectively achieved.
Unless otherwise defined, all terms used herein are intended to have the meanings commonly understood by those skilled in the art.
The described embodiments of the present invention are intended to be illustrative only and not to limit the scope of the invention, and various other alternatives, modifications, and improvements may be made by those skilled in the art within the scope of the invention, and therefore the invention is not limited to the above embodiments but only by the claims.

Claims (16)

1. An anti-extraction pharmaceutical composition comprises an active ingredient and pharmaceutical excipients, and is characterized in that the active ingredient comprises ephedrine substances or pharmaceutically acceptable salts thereof, and the pharmaceutical excipients comprise high molecular polymer framework materials and purification influencing additives; wherein the high molecular polymer framework material comprises the following components in percentage by mass of 1-10: 1-20: 1, cellulose derivative and povidone, wherein the cellulose derivative is selected from one or more of microcrystalline cellulose, methyl cellulose, hydroxypropyl cellulose and hydroxypropyl methylcellulose, and the purification influencing additive is prepared from cholesterol and tween 80 in a ratio of 0.1-10: 1 or the purification influencing additive consists of cholesterol and lecithin in a mass ratio of 0.1-10: 1 mass ratio; the mass ratio of the ephedrine substance or the pharmaceutically acceptable salt thereof to the high molecular polymer framework material to the purification influencing additive is 1:1 to 15:0.01 to 5.
2. The extraction-preventing pharmaceutical composition according to claim 1, wherein the mass ratio of ephedrine substance or pharmaceutically acceptable salt thereof, the high molecular polymer matrix material and the purification-influencing additive is 1:1 to 8: 0.02-3.
3. The extraction-preventing pharmaceutical composition according to claim 1, wherein when the purification-affecting additive consists of cholesterol and tween 80, the mass ratio of the cholesterol to the tween 80 is 0.2-5: 1, a step of; or when the purification influencing additive consists of cholesterol and lecithin, the mass ratio of the cholesterol to the lecithin is 0.2-5: 1.
4. the extraction-preventing pharmaceutical composition according to claim 1, wherein the mass ratio of the polyoxyethylene, the cellulose derivative and the povidone in the high molecular polymer matrix material is 1.5 to 6:1 to 10:1.
5. the anti-extraction pharmaceutical composition according to claim 1, wherein the cellulose derivative is selected from hydroxypropyl cellulose and/or hypromellose.
6. The extraction-preventing pharmaceutical composition according to claim 1, wherein the pharmaceutical excipients further comprise an auxiliary agent, and the mass ratio of the auxiliary agent to the ephedrine substance or pharmaceutically acceptable salt thereof is 0.01-1.5: 1, wherein the auxiliary agent is selected from ferric citrate and/or vitamin E.
7. The extraction preventing pharmaceutical composition according to claim 6, wherein the mass ratio of the auxiliary agent to the ephedrine compound or pharmaceutically acceptable salt thereof is 0.02 to 0.5:1.
8. the extraction-preventing pharmaceutical composition according to claim 6, wherein the auxiliary agent consists of ferric citrate and vitamin E in a mass ratio of 1:1 to 10.
9. The extraction-preventing pharmaceutical composition according to claim 8, wherein the auxiliary agent consists of ferric citrate and vitamin E in a mass ratio of 1:2 to 5.
10. The anti-extraction pharmaceutical composition according to claim 1, wherein the ephedrine is selected from one or more of ephedrine, pseudoephedrine, racemic ephedrine, norephedrine, methamphetamine, ephedra extract powder; the pharmaceutically acceptable salt is selected from one or more of hydrochloride, sulfate, fumarate and maleate.
11. The anti-extraction pharmaceutical composition according to any one of claims 1-10, wherein the active ingredient further comprises one or more of the following ingredients: acetaminophen, chlorpheniramine maleate, chloromatamine fumarate, azatadine maleate, chloramphenicol maleate, dextromethorphan hydrobromide, diphenhydramine hydrochloride, naproxen sodium, atorvastatin, loratadine hydrochloride, thiazine hydrochloride, ibuprofen, cetirizine, fexofenadine hydrochloride, triprolidine hydrochloride, and guaifenesin.
12. A pharmaceutical formulation comprising the anti-extraction pharmaceutical composition of any one of claims 1-11.
13. The pharmaceutical formulation of claim 12, further comprising one or more of a filler, a binder, a disintegrant, a coating, a salt, a lubricant.
14. The pharmaceutical formulation according to claim 13, wherein the filler is selected from one or more of lactose, sucrose, xylitol, sorbitol, calcium sulfate, mannitol, dextrin, starch, diatomaceous earth, kaolin; the adhesive is selected from one or more of pregelatinized starch and water-soluble resin; the disintegrating agent is one or more selected from crospovidone, low-substituted hydroxypropyl cellulose, croscarmellose sodium, croscarmellose and sodium carboxymethyl starch; the coating agent is one or more selected from acrylic resin, cellulose acetate phthalate, polyvinyl alcohol phthalate and cellulose acetate trimellitate; the salt is one or more selected from ferrous sulfate, ferrous chloride, ferrous nitrate, ferrous phosphate, ferrous gluconate, zinc sulfate, zinc chloride, zinc nitrate, zinc phosphate and zinc gluconate; the lubricant is one or more selected from magnesium stearate, aerosil, talcum powder, calcium stearate, polyethylene glycol 6000 and methyl silicone oil.
15. The pharmaceutical formulation according to any one of claims 12-14, wherein the pharmaceutical formulation is a solid formulation.
16. The pharmaceutical formulation of claim 15, wherein the pharmaceutical formulation is a tablet, capsule, granule, powder, or drop pill.
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6136864A (en) * 1996-04-10 2000-10-24 Warner-Lambert Company Denaturants for sympathomimetic amine salts
CN1513439A (en) * 2003-06-05 2004-07-21 南京长澳医药科技有限公司 Slow release medicine of pseudo-ephedrine hydrochloride
CN102018712A (en) * 2010-12-30 2011-04-20 东莞广州中医药大学中医药数理工程研究院 Pharmaceutical composition comprising dextromethorphan, chlorpheniramine and pseudoephedrine and preparation method thereof
CN110215521A (en) * 2019-06-19 2019-09-10 江苏长泰药业有限公司 Inhibit composition and its application that pseudoephedrine hydrochloride is extracted from solvent

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE102004045037A1 (en) * 2004-09-15 2006-03-16 Basf Ag Pharmaceutical dosage forms with difficult extractability of a sympathomimetic from the dosage form

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6136864A (en) * 1996-04-10 2000-10-24 Warner-Lambert Company Denaturants for sympathomimetic amine salts
CN1513439A (en) * 2003-06-05 2004-07-21 南京长澳医药科技有限公司 Slow release medicine of pseudo-ephedrine hydrochloride
CN102018712A (en) * 2010-12-30 2011-04-20 东莞广州中医药大学中医药数理工程研究院 Pharmaceutical composition comprising dextromethorphan, chlorpheniramine and pseudoephedrine and preparation method thereof
CN110215521A (en) * 2019-06-19 2019-09-10 江苏长泰药业有限公司 Inhibit composition and its application that pseudoephedrine hydrochloride is extracted from solvent

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