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CN114073690B - Extraction-preventing pharmaceutical composition containing amino acid and preparation thereof - Google Patents

Extraction-preventing pharmaceutical composition containing amino acid and preparation thereof Download PDF

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Publication number
CN114073690B
CN114073690B CN202010804362.1A CN202010804362A CN114073690B CN 114073690 B CN114073690 B CN 114073690B CN 202010804362 A CN202010804362 A CN 202010804362A CN 114073690 B CN114073690 B CN 114073690B
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China
Prior art keywords
extraction
pharmaceutical composition
mass ratio
composition according
ephedrine
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CN114073690A (en
Inventor
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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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
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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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    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
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    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
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Abstract

The invention provides an extraction-preventing pharmaceutical composition containing amino acid, 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 effectively achieve the aims of preventing toxin production and abuse, the effect is obviously better than that of similar products sold in the market, and the raw materials used by the invention are cheap and easy to obtain, and the preparation method is simple and convenient and has economic and social values.

Description

Extraction-preventing pharmaceutical composition containing amino acid and preparation thereof
Technical Field
The invention relates to the field of medicines, in particular to an extraction-preventing pharmaceutical composition containing amino acid 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 one or more of amino acid and 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 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 selected from one or more of Tween 80, lecithin and poloxamer. In some preferred embodiments, the purification-affecting additive consists of an amino acid and tween 80, the mass ratio of which can be 0.1 to 10:1, a step of; in some more preferred embodiments, the mass ratio of the amino acid to the tween 80 may be from 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.
The amino acid in the anti-extraction pharmaceutical composition provided by the invention can be selected from any kind of amino acid, including natural amino acid and non-natural amino acid, can be single kind of amino acid, and can be a mixture of any kind of amino acid. In some preferred embodiments, the amino acid may be selected from phenylalanine and/or proline. When the amino acid is selected from phenylalanine and proline, the mass ratio of phenylalanine to proline 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 some more preferred embodiments, the mass ratio of phenylalanine to proline may be 0.5 to 2:1.
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 pharmaceutical composition of the invention, including but not limited to a filling agent, a binding agent, a disintegrating agent, a coating agent, salts, a lubricant and the like, and the type of the carrier can also be any pharmaceutically acceptable type, for example, the filling agent comprises 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 extraction-preventing 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. In addition, even if the extract is separated, the purity of the active ingredient in the extract is lower or the recovery rate is lower, so that the purposes of preventing toxin production and preventing drug abuse can be effectively achieved, and the effect is obviously better than that of similar products on 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
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) The solid materials of pseudoephedrine hydrochloride, phenylalanine, hydroxypropyl cellulose, vitamin E, ferric citrate and povidone are placed 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, proline, 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 1.42%).
4) And (3) dry finishing: finishing parameters: 2.0mm screen mesh sieving and granulating, motor rotation speed: 400rpm. (yield of dry particles 89%).
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 analysis experiment of ingredients to cause effects of emulsification, swelling, gelation, etc
50mg of the materials (specific ingredients are shown in Table 3) 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 an emulsifying layer (comprising swellings and gels) is lower than 30 percent of the total volume, and layering is carried out at about 90 percent within 5 hours, so that the strong emulsifying phenomenon is realized;
"+++": after extraction, standing for 15 minutes, wherein the volume of the emulsion layer (comprising swellings and gels) is higher than 30 percent of the total volume, and about 90 percent of the emulsion layer is layered within 10 hours after standing, so that the emulsion layer has a strong emulsion phenomenon;
"++++": after extraction, the emulsion layer (including swellings and gels) had a volume of greater than 65% of the total volume and was not fully layered within 10 hours of standing for 15 minutes.
TABLE 3 analysis of key ingredients leading to effects of emulsification, swelling, gelation, etc
The expression "emulsification" in the table actually means the combined effects of emulsification, swelling, gelation, etc.
The results in Table 3 show that the main materials in the pharmaceutical composition of the invention have certain emulsifying property, swelling property or gelling property, which is the basis of the composition having strong emulsifying, swelling, gelling and other capabilities during extraction. In addition, the combination of materials including amino acid and tween 80 achieved a stronger emulsifying, swelling and gelling capacity relative to the single material (the same total amount used). Therefore, the pharmaceutical composition of the invention can generate a strong blocking effect in the extraction process, and successfully set the first heavy checkpoint. When most common toxicants face the first heavy checkpoint, the extraction behavior has to be abandoned due to no expert knowledge, so that the effect of inhibiting the extraction behavior is achieved.
Test example 2 evaluation experiment of extraction Effect
Extraction solvent: water, ethanol and methylene dichloride.
The extraction method comprises the following steps: as shown in table 4.
A) Weighing 2.0g of the composition sample, grinding, adding the mixture into a 100mL beaker, adding 50mL of purified water, stirring for 10min, carrying out suction filtration, concentrating the filtrate, and drying to obtain a dried product.
B) Weighing 2.0g of the composition sample, grinding, adding the mixture into a 100mL beaker, adding 30mL of ethanol, stirring for 10min, carrying out suction filtration, adding 20mL of ethanol to wash a filter cake, concentrating and drying the filtrate to obtain a dried product.
C) 2.0g of a sample of the composition of the example was weighed, ground, added to a 100mL beaker, 40mL of purified water was added, stirred for 10min, 3mL of 2M NaOH solution was added, then transferred to a separatory funnel, 30mL of dichloromethane was added, shaking vigorously was performed, after delamination, the organic layer was separated, concentrated and dried.
Table 4 extraction method
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:
TABLE 5 summary of the extraction results
Note 1: recovery of pseudoephedrine hydrochloride, recovery of pseudoephedrine free base, recovery = extract weight x purity ∈weight; y represents the presence of emulsifying/swelling/gelling effects during extraction.
And (2) 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.
As can be seen from the extraction results of table 5, when the pharmaceutical composition of the present invention is extracted, the purity and recovery rate of the active ingredient extract are both lower than 50%, and the lower purity and recovery rate are unfavorable for the subsequent experiments, so that the cost of toxicity production is greatly increased, and the toxicity producer is forced to abandon the toxicity production plan, thereby achieving excellent extraction prevention effect. For the new Kangtai of the same kind of medicines sold at present, the purity and recovery rate of the active ingredient extract are higher, and the extraction preventing effect is poor.
As can be seen from the results of the above test examples 1 and 2, the pharmaceutical composition of the present invention has the "dual-checkpoint" extraction preventing function, wherein the "checkpoint" means that the extraction process has strong emulsification, swelling, gelation and other effects, and thus the separation is difficult, so that a plurality of detoxifiers have to give up the extraction behavior (the results of table 3); "checkpoint" two means that even though the drug producer had barely separated the extract, lower purity, recovery was not beneficial for subsequent transformation experiments (results in Table 5). Therefore, the pharmaceutical composition provided by the invention has multiple extraction prevention functions, and can effectively achieve the purposes of extraction prevention and abuse prevention.
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 (18)

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 amino acid and tween 80 in a ratio of 0.1-10: 1, wherein the amino acid is selected from phenylalanine and/or proline; 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 the mass ratio of the amino acid to the tween 80 is 0.2 to 5:1.
4. the anti-extraction pharmaceutical composition according to claim 1, wherein when the amino acid is selected from phenylalanine and proline, the mass ratio of phenylalanine to proline is 0.2 to 5:1.
5. the extraction preventing pharmaceutical composition according to claim 4, wherein when the amino acid is selected from phenylalanine and proline, the mass ratio of phenylalanine to proline is 0.5 to 2:1.
6. 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.
7. the anti-extraction pharmaceutical composition according to claim 1, wherein the cellulose derivative is selected from hydroxypropyl cellulose and/or hypromellose.
8. 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, a step of; the auxiliary agent is selected from ferric citrate and/or vitamin E.
9. The extraction preventing pharmaceutical composition according to claim 8, wherein the mass ratio of the auxiliary agent to the ephedrine-like substance or pharmaceutically acceptable salt thereof is 0.02 to 0.5:1.
10. 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 1:1 to 10.
11. The extraction-preventing pharmaceutical composition according to claim 10, wherein the auxiliary agent consists of ferric citrate and vitamin E in a mass ratio of 1:2 to 5.
12. 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.
13. The anti-extraction pharmaceutical composition according to any one of claims 1-12, 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.
14. A pharmaceutical formulation comprising the anti-extraction pharmaceutical composition of any one of claims 1-13.
15. The pharmaceutical formulation of claim 14, further comprising one or more of a filler, a binder, a disintegrant, a coating, a salt, a lubricant.
16. The pharmaceutical formulation according to claim 15, 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.
17. The pharmaceutical formulation according to any one of claims 14 to 16, wherein the pharmaceutical formulation is a solid formulation.
18. The pharmaceutical formulation of claim 17, wherein the pharmaceutical formulation is a tablet, capsule, granule, powder, or drop pill.
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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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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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