CN114073690A - Amino acid-containing anti-extraction pharmaceutical composition and preparation thereof - Google Patents

Amino acid-containing anti-extraction pharmaceutical composition and preparation thereof Download PDF

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Publication number
CN114073690A
CN114073690A CN202010804362.1A CN202010804362A CN114073690A CN 114073690 A CN114073690 A CN 114073690A CN 202010804362 A CN202010804362 A CN 202010804362A CN 114073690 A CN114073690 A CN 114073690A
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extraction
pharmaceutical composition
ephedrine
pharmaceutical
amino acid
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CN114073690B (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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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/17—Gnetophyta, e.g. Ephedraceae (Mormon-tea family)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof

Abstract

The invention provides an anti-extraction pharmaceutical composition containing amino acid, which comprises an active ingredient and pharmaceutical excipients, wherein the active ingredient comprises ephedrine substances or pharmaceutically acceptable salts thereof, and the pharmaceutical excipients comprise high molecular polymer framework materials and purification-affecting additives. The invention also provides a pharmaceutical preparation, which comprises the pharmaceutical composition provided by the invention. The anti-extraction pharmaceutical composition and the pharmaceutical preparation can effectively achieve the purposes of preventing poison control and abuse, have obviously better effects than similar products sold in the market, and have cheap and easily obtained raw materials, simple and convenient preparation method and very high economic and social values.

Description

Amino acid-containing anti-extraction pharmaceutical composition and preparation thereof
Technical Field
The invention relates to the field of medicines, in particular to an amino acid-containing anti-extraction pharmaceutical composition and a pharmaceutical preparation containing the same.
Background
The easily-made chemicals refer to substances regulated by national regulations, such as precursors, raw materials, chemical auxiliaries and the like which can be used for manufacturing drugs. The ephedrine substance is a kind of chemicals which are easy to prepare poison and specified by China, and mainly comprises pseudoephedrine hydrochloride, pseudoephedrine sulfate, ephedrine hydrochloride, ephedrine sulfate, phenylpropanolamine hydrochloride and the like.
Pseudoephedrine hydrochloride is the most commonly used agonist of sympathomimetic nervous system, and is widely used for treating respiratory diseases, preventing cold and the like. Pseudoephedrine hydrochloride can also be used as a raw material for synthesizing drugs, and methamphetamine (commonly known as methamphetamine) is obtained through reaction. Many drug makers purchase a commercially available product such as neocombatadine, gakuttuyn, etc. containing pseudoephedrine hydrochloride, obtain relatively pure pseudoephedrine through simple extraction, and use it for manufacturing methamphetamine. An important step in the extraction of pseudoephedrine is the 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 pharmaceutical composition design ideas are currently reported, summarized as follows: (1) and (3) preventing damage: before the medicine is illegally applied, the medicine is firstly crushed, and the crushing, crushing or breaking strength of the preparation is increased, so that a poison maker cannot crush the medicine by a conventional tool, and the probability of illegal application is 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) And (3) transformation prevention: adding proper additive to block the chemical reaction of pseudoephedrine to methamphetamine.
Therefore, the current research mainly aims to increase the breaking strength of the preparation or add interference components to interfere the processes of extracting, converting and the like of pseudoephedrine or other similar medicines, thereby increasing the difficulty of virus preparation of virus makers. Although some related techniques have been reported, the obtained effects are still quite limited.
Disclosure of Invention
In order to overcome the defects in the prior art, the invention aims to provide an anti-extraction pharmaceutical composition which can effectively prevent ephedrine active ingredients from being extracted, thereby effectively achieving the aim of preventing drugs from being abused.
It is another object of the present invention to provide a pharmaceutical formulation.
The anti-extraction pharmaceutical composition provided by the invention comprises an active ingredient and pharmaceutical excipients, wherein the active ingredient comprises ephedrine substances or pharmaceutically acceptable salts thereof, and the pharmaceutical excipients comprise high molecular polymer framework materials and purification-affecting additives; wherein the high molecular polymer skeleton material comprises polyoxyethylene, povidone and cellulose derivatives, and the purification influencing additive comprises amino acid and one or more of the following surfactants: tween 80, lecithin, poloxamer, sodium lauryl sulfate, stearic acid, oleic acid, lauric acid, sodium dioctyl sulfosuccinate, sodium glycocholate, glyceryl monostearate or mercurial.
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 skeleton material and the purification influencing additive, so that the separation of active ingredients is difficult, the extraction time is obviously prolonged, serious extraction obstacles are produced, and even if the extract is separated out, the purity of the active ingredients is low, the recovery rate is low, so that the extraction cost is greatly increased, and the aims of preventing poison control and preventing drug abuse can be effectively achieved.
In the anti-extraction pharmaceutical composition provided by the invention, the weight ratio of the ephedrine substance or the pharmaceutically acceptable salt thereof, the high molecular polymer skeleton material and the purification-affecting additive can be 1: 1-15: 0.01 to 5. In some preferred embodiments, the ephedrine substance or the pharmaceutically acceptable salt thereof, the high molecular polymer matrix material and the purification-affecting additive may be present in a mass ratio of 1: 1-8: 0.02 to 3. Specifically, when the amount of the ephedrine substance 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 combination of parts by weight, 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 combination of parts by weight.
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, and the mass ratio of the amino acid to the tween 80 may be 0.1 to 10: 1; in some more preferred embodiments, the mass ratio of the amino acid 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 mass ratio interval combination.
In the anti-extraction pharmaceutical composition provided by the invention, the amino acid can be selected from any kind, including natural amino acid and unnatural amino acid, and can be a single kind of amino acid or 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 the phenylalanine to the proline can be 0.2-5: 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 mass ratio interval combination; in some more preferred embodiments, the mass ratio of the phenylalanine to the proline may be 0.5 to 2: 1.
in the anti-extraction pharmaceutical composition provided by the invention, in the high molecular polymer skeleton 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: 1-10: 1. specifically, when povidone is 1 part by weight in the high molecular polymer matrix material, the amount of 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. parts by weight or any combination of parts by weight intervals, and the amount of 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. parts by weight or any combination of parts by weight intervals.
In some preferred embodiments, the cellulose derivative may be selected from one or more of microcrystalline cellulose, methylcellulose, hydroxypropylcellulose, and 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 material can further comprise an auxiliary agent, and the mass ratio of the auxiliary agent 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 mass ratio interval combination. In some preferred embodiments, the mass ratio of the auxiliary agent to the ephedrine or pharmaceutically acceptable salt thereof may be 0.02 to 0.5: 1.
in some preferred embodiments, the adjunct 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 of the ferric citrate to the vitamin E can 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 mass ratio interval combination. In some further preferred embodiments, the mass ratio of the ferric citrate and 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 selected from one or more of ephedrine, pseudoephedrine, racemic ephedrine, norephedrine, methylephedrine and ephedra extract powder, and the pharmaceutically acceptable salt can be any form of salt, such as inorganic acid salt or organic acid salt, preferably selected from one or more of hydrochloride, sulfate, fumarate and maleate.
In the anti-extraction pharmaceutical composition provided by the invention, the active ingredient can also comprise other active ingredients besides ephedrine substances or pharmaceutically acceptable salts thereof, especially active ingredients used in medicaments for treating respiratory diseases, anti-cold and the like, including but not limited to one or more of the following ingredients: acetaminophen, chlorpheniramine maleate, clemastine fumarate, azatadine maleate, chloramphenicol maleate, dextromethorphan hydrobromide, diphenhydramine hydrochloride, naproxen sodium, atorvastatin, loratadine, 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 above technical schemes.
The dosage of the pharmaceutical composition of the pharmaceutical preparation provided by the invention can be selected by those skilled in the art according to factors such as different dosage forms and different applications. In some preferred embodiments, the percentage by mass of the ephedrine substance or the pharmaceutically acceptable salt thereof in the pharmaceutical preparation may be 3-30%; in some more preferred embodiments, the percentage by mass of the ephedrine substance or the pharmaceutically acceptable salt thereof in the pharmaceutical preparation may be 10 to 30%.
The pharmaceutical preparation provided by the invention can also comprise any pharmaceutically acceptable carrier besides the pharmaceutical composition of the invention, including but not limited to filler, binder, disintegrant, coating agent, salt, lubricant, etc., and the type of the carrier can also be any pharmaceutically acceptable type, for example, the filler includes but not limited to 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 disintegrant comprises one or more of but is not limited to crospovidone, low-substituted hydroxypropyl cellulose, croscarmellose sodium, croscarmellose and sodium carboxymethyl starch; the coating agent includes, but is not limited to, one or more of acrylic resin, cellulose acetate phthalate, polyvinyl alcohol phthalate, 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, superfine silica gel powder, 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 preparation can be a solid preparation, including but not limited to tablets, capsules, granules, powders, drop pills, and the like.
The pharmaceutical preparation provided by the invention can be prepared by selecting the processes and equipment well known in the art according to different dosage forms.
The anti-extraction pharmaceutical composition and the pharmaceutical preparation provided by the invention have the following advantages:
the anti-extraction pharmaceutical composition and the pharmaceutical preparation of the invention can generate strong effects of emulsification, swelling, gelation and the like in the extraction process, thereby causing difficult separation of ephedrine active ingredients. In addition, even if the extract is separated, the purity of the active ingredients in the extract is low or the recovery rate is low, so that the aims of preventing poison control and drug abuse can be effectively fulfilled, and the effect is obviously better than that of similar products sold in the market.
The raw materials used by the anti-extraction pharmaceutical composition and the pharmaceutical preparation are low in price 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 solution of the present invention is further described in detail with reference to the following specific examples.
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
Figure BDA0002625835330000051
Figure BDA0002625835330000061
TABLE 2 apparatus
Device name Model number Manufacturer of the product
Granulating machine G6 Shenzhen city Xinyite Teke Limited
FZ series disintegrating and granulating machine 150 type Jiangyin Lingling mechanical manufacturing Co., Ltd
Hot air circulation oven DHG3132A Shanghai essence macro 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 all percentages by mass, unless otherwise specified.
Example 1
The composition of example 1 (composition 1) was formulated as follows:
Figure BDA0002625835330000062
composition samples were prepared manually for extraction experiments and assay. According to the formula, the materials are added in 30 times.
The preparation process comprises the following steps:
1) placing solid materials of pseudoephedrine hydrochloride, phenylalanine, hydroxypropyl cellulose, vitamin E, ferric citrate and polyvidone in a small tray, and manually mixing to obtain a mixture.
2) Preparing Tween 80 into a 7 wt% aqueous solution, firstly spraying a half volume of Tween 80 solution into the mixture obtained in the step 1), and gently stirring; then adding polyoxyethylene for secondary mixing, spraying the rest half volume of Tween 80 solution to obtain soft material, and drying in hot air circulation oven (60 deg.C, 8 hr).
3) And grinding and crushing the dried soft material for later use.
Example 2
The composition of example 2 (composition 2) was formulated as follows:
Figure BDA0002625835330000071
the procedure was as in example 1.
Example 3
Example 3 composition (composition 3) was formulated as follows:
Figure BDA0002625835330000072
Figure BDA0002625835330000081
the procedure was as in example 1.
Example 4
The composition of example 4 (composition 4) was formulated as follows:
Figure BDA0002625835330000082
the procedure was as in example 1.
Example 5
Example 5 composition (composition 5) was formulated as follows:
Figure BDA0002625835330000083
the procedure was as in example 1.
Example 6
The composition of example 6 (composition 6) was formulated as follows:
Figure BDA0002625835330000091
the procedure was as in example 1.
Example 7
The composition of example 7 (composition 7) was formulated as follows:
Figure BDA0002625835330000092
the procedure was as in example 1.
Example 8
The composition of example 8 (composition 8) was formulated as follows:
Figure BDA0002625835330000093
the procedure was as in example 1.
Example 9
The composition of example 9 (composition 9) was formulated as follows:
Figure BDA0002625835330000101
the procedure was as in example 1.
Example 10
The composition of example 10 (composition 10) was formulated as follows:
Figure BDA0002625835330000102
the procedure was as in example 1.
Example 11
The composition of example 11 (composition 11) was formulated as follows:
Figure BDA0002625835330000103
Figure BDA0002625835330000111
the procedure was as in example 1.
Example 12
The composition of example 12 (composition 12) was formulated as follows:
Figure BDA0002625835330000112
the procedure was as in example 1.
Example 13
The composition of example 13 (composition 13) was formulated as follows:
Figure BDA0002625835330000113
Figure BDA0002625835330000121
the procedure was as in example 1.
Example 14
The composition of example 14 (composition 14) was formulated as follows:
Figure BDA0002625835330000122
the procedure was as in example 1.
Example 15
The formulation of example 15 is as follows:
Figure BDA0002625835330000123
note: the above table is a unit formulation prescription.
Formulation development was carried out with the recipe of example 15.
1. And (3) tablet preparation:
1) mixing: according to 1000 times of the prescription amount of a unit preparation, pseudoephedrine hydrochloride, chlorphenamine maleate, proline, microcrystalline cellulose, hydroxypropyl cellulose, povidone, vitamin E and croscarmellose sodium are taken and sieved. Adding a high-speed mixing granulator for mixing, mixing parameters, and stirring: 5r/s, rotating speed of a granulating cutter: 7/s, run for 3 min.
2) Preparing soft materials and wet granules: preparing 10% Tween 80 into 10% water solution, spraying into the mixture, and wet mixing at high speed for granulating. Parameters of a granulator: stirring: running for 2min at 6 r/s; a granulating cutter: 8/s, run for 1 min.
3) Wet granulation and drying: and (3) finishing parameters: sieving and granulating by using a 2.0mm screen, wherein the rotating speed of a motor is as follows: 400 rpm. Drying parameters: the soft mass was dried at 60 ℃ for 3h (moisture 1.42%).
4) Dry granulation: and (3) finishing parameters: sieving and granulating by using a 2.0mm screen, wherein the rotating speed of a motor is as follows: 400 rpm. (yield of dry granules 89%).
5) Total mixing: and adding the dry particles, polyoxyethylene and talcum powder into an HD three-dimensional motion mixer, and mixing at the rotating speed of 10r/min for 3 min.
6) Tabletting: a mould: 14 × 6.3 punches, capsule punches. Piece weight: 300mg, hardness: 120N, respectively.
2. Granules and capsules:
proceeding to step 4) as described above for the tablet procedure, the dry granules, polyoxyethylene, are then added to the HD three-dimensional motion mixer and mixed. The rotating speed is 10r/min, and the mixture is mixed for 3 min.
Subpackaging the obtained granules to obtain granules.
And filling the obtained granules into capsules to obtain capsules.
Test example 1 composition analysis experiment for inducing emulsification, swelling, gelation and the like
50mg of materials (specific components are shown in table 3) are weighed respectively and put into a small centrifuge tube, 1mL of water and 1mL of dichloromethane are added respectively, the mixture is shaken for 10 seconds and kept stand, and the emulsification and layering conditions are observed.
The results are shown below:
"-": after extraction, the mixture is kept stand for 5 minutes, so that obvious layering can be realized, and no emulsification phenomenon exists;
"+": standing for 15 minutes after extraction, wherein the volume of an emulsion layer (comprising swelling matters and gelatination matters) is less than 20% of the total volume, and completely layering within 5 h;
"++": after extraction, the mixture is kept stand for 15 minutes, the volume of an emulsion layer (comprising swelling matters and gelatination matters) is less than 30 percent of the total volume, and the emulsion layer is layered by about 90 percent within 5 hours of standing, so that a strong emulsification phenomenon is generated;
"+++": after extraction, the mixture is kept stand for 15 minutes, the volume of an emulsion layer (comprising swelling matters and gelatination matters) is higher than 30 percent of the total volume, and about 90 percent of the emulsion layer is layered after being kept stand for 10 hours, so that the strong emulsification phenomenon exists;
"++++": and standing for 15 minutes after extraction, wherein the volume of an emulsion layer (including swelling matters and gel matters)) is more than 65% of the total volume, and the emulsion layer is not completely separated within 10 hours of standing.
TABLE 3 analysis of key ingredients leading to emulsification, swelling, gelling, etc. effects
Figure BDA0002625835330000141
In the table, "emulsification" actually refers to the combined effects of emulsification, swelling, gelation, and the like.
The results in table 3 show that the main materials in the pharmaceutical composition of the present invention have certain emulsifiability, swellability or colloidibility, which is the basis for the composition to have strong emulsifiability, swellability, colloidibility, etc. during extraction. Furthermore, the combination of materials comprising amino acid and tween 80 gives a stronger emulsifying, swelling and gelling capacity than the single materials (the same total amount used). Thus, the pharmaceutical composition of the present invention is able to produce a strong "stop" effect during the extraction process, successfully setting the first heavy "checkpoint". When most of ordinary virus makers face the first important 'checkpoint', the extraction behavior has to be abandoned due to no professional knowledge, and the effect of inhibiting the extraction behavior is achieved.
Test example 2 evaluation experiment of extraction Effect
Extracting solvent: water, ethanol, dichloromethane.
The extraction method comprises the following steps: as shown in table 4.
A) Weighing 2.0g of the composition sample of the embodiment, grinding, adding into a 100mL beaker, adding 50mL of purified water, stirring for 10min, filtering, concentrating the filtrate, and drying to obtain a dry product.
B) Weighing 2.0g of the composition sample of the embodiment, grinding, adding into a 100mL beaker, adding 30mL of ethanol, stirring for 10min, filtering, adding 20mL of ethanol, washing a filter cake, concentrating the filtrate, and drying to obtain a dry product.
C) Weighing 2.0g of the composition sample of the example, grinding, adding into a 100mL beaker, adding 40mL of purified water, stirring for 10min, adding 3mL of 2M NaOH solution, transferring into a separating funnel, adding 30mL of dichloromethane, shaking vigorously, separating the organic layer after layering, concentrating and drying.
TABLE 4 extraction methods
Figure BDA0002625835330000151
The samples extracted in 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 analysis was as follows:
1. apparatus and device: waters spherisorb, SCX,4.6 multiplied by 150mm, 5-mum particle size or performance equivalent high performance liquid chromatograph, liquid pump, UV or PDA detector and temperature controllable column oven, 0.45-mum water system filter membrane.
2. Mobile phase: ammonium acetate buffer solution 600mL + acetonitrile 400mL, mixing, degassing. Wherein, the preparation of ammonium acetate buffer salt solution (20 mM): taking 3.08g of ammonium acetate to 2000mL of water, transferring 1.0mL of triethylamine, adjusting the pH value to 5.0 +/-0.05 by using acetic acid, uniformly stirring, and filtering by using a 0.45-mum water system filter membrane.
3. Chromatographic conditions are as follows:
Figure BDA0002625835330000152
Figure BDA0002625835330000161
TABLE 5 summary of the extraction results
Figure BDA0002625835330000162
Note 1: a, the recovery rate of pseudoephedrine hydrochloride, b, the recovery rate of pseudoephedrine free alkali, wherein the recovery rate is the weight of the extract multiplied by the purity divided by the original weight; y represents the emulsification/swelling/gelling effect present during extraction.
Note 2: the new kangtaike compound pseudoephedrine hydrochloride sustained-release capsule produced by the company of Mitsuik of Mitsubishi of New kangtaike is extracted from the granules in the capsule. Each granule contains 90 mg of pseudoephedrine hydrochloride and 4 mg of chlorpheniramine maleate. The auxiliary materials comprise: starch, sucrose, hydroxypropyl methylcellulose, ethyl cellulose, opadry pink spray and opadry yellow spray.
As can be seen from the extraction results in 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 not favorable for the subsequent experiments, so that the cost of preparing the drug is greatly increased, and the drug manufacturer is forced to abandon the drug preparation plan, thereby achieving the excellent anti-extraction effect. For the similar medicine Xinkangtaike sold in the market at present, the purity and the recovery rate of the active ingredient extract are higher, the anti-extraction effect is poorer, and the pharmaceutical composition of the invention is obviously better than the similar medicine sold in the market at present in the aspect of the anti-extraction effect.
As can be seen from the results of the foregoing test examples 1 and 2, the pharmaceutical composition of the present invention has a "dual checkpoint" anti-extraction function, wherein "checkpoint" means that strong emulsification, swelling, gelation, etc. effects are generated during the extraction process, resulting in difficult separation, so that most drug makers have to abandon the extraction process (the results in table 3); the second "checkpoint" means that even if the drug manufacturer does not isolate the extract, the lower purity and recovery rate are not favorable for the subsequent transformation experiment (results in Table 5). Therefore, the pharmaceutical composition provided by the invention has multiple anti-extraction functions, and can effectively achieve the purposes of extraction prevention and abuse prevention.
Unless otherwise defined, all terms used herein have the meanings commonly understood by those skilled in the art.
The described embodiments of the present invention are for illustrative purposes only and are not intended to limit the scope of the present invention, and those skilled in the art may make various other substitutions, alterations, and modifications within the scope of the present invention, and thus, the present invention is not limited to the above-described embodiments but only by the claims.

Claims (10)

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-affecting additives; wherein the high molecular polymer skeleton material comprises polyoxyethylene, povidone and cellulose derivatives, and the purification influencing additive comprises amino acid and one or more of the following surfactants: tween 80, lecithin, poloxamer, sodium lauryl sulfate, stearic acid, oleic acid, lauric acid, sodium dioctyl sulfosuccinate, sodium glycocholate, glyceryl monostearate or mercurial.
2. The anti-extraction pharmaceutical composition according to claim 1, wherein the weight ratio of the ephedrine substance or the pharmaceutically acceptable salt thereof, the high molecular polymer matrix material and the purification-affecting additive is 1: 1-15: 0.01 to 5; preferably 1: 1-8: 0.02 to 3.
3. The anti-extraction pharmaceutical composition according to claim 1 or 2, wherein the surfactant is selected from one or more of tween 80, lecithin, poloxamer; preferably, the influence purification additive consists of amino acid and tween 80, and the mass ratio of the amino acid to the tween 80 is 0.1-10: 1, preferably 0.2-5: 1; more preferably, the amino acid is selected from phenylalanine and/or proline, and when the amino acid is selected from phenylalanine and proline, the mass ratio of the phenylalanine to the proline is 0.2-5: 1, preferably 0.5-2: 1.
4. the extraction-preventing pharmaceutical composition according to any one of claims 1 to 3, wherein the mass ratio of the polyoxyethylene, the cellulose derivative and the povidone in the high molecular polymer matrix material is 1 to 10: 1-20: 1; preferably 1.5-6: 1-10: 1; preferably, the cellulose derivative is selected from one or more of microcrystalline cellulose, methylcellulose, hydroxypropyl cellulose and hydroxypropyl methylcellulose; more preferably, the cellulose derivative is selected from hydroxypropyl cellulose and/or hypromellose.
5. The anti-extraction pharmaceutical composition according to any one of claims 1 to 4, wherein the pharmaceutical excipients further comprise an auxiliary agent, and the mass ratio of the auxiliary agent to the ephedrine compound or the pharmaceutically acceptable salt thereof is 0.01-1.5: 1; preferably 0.02-0.5: 1; preferably, the auxiliary agent is selected from ferric citrate and/or vitamin E; more preferably, the auxiliary agent consists of ferric citrate and vitamin E, and the mass ratio of the ferric citrate to the vitamin E is 1: 1-10, preferably 1: 2 to 5.
6. The anti-extraction pharmaceutical composition according to any one of claims 1 to 5, wherein the ephedrine substance is selected from one or more of ephedrine, pseudoephedrine, racemic ephedrine, demethyl ephedrine, methyl ephedrine, and ephedra extract powder; the pharmaceutically acceptable salt is selected from one or more of hydrochloride, sulfate, fumarate and maleate.
7. The anti-extraction pharmaceutical composition according to any one of claims 1 to 6, wherein the active ingredient further comprises one or more of the following ingredients: acetaminophen, chlorpheniramine maleate, clemastine fumarate, azatadine maleate, chloramphenicol maleate, dextromethorphan hydrobromide, diphenhydramine hydrochloride, naproxen sodium, atorvastatin, loratadine, thiazine hydrochloride, ibuprofen, cetirizine, fexofenadine hydrochloride, triprolidine hydrochloride, and guaifenesin.
8. A pharmaceutical preparation comprising the anti-extraction pharmaceutical composition according to any one of claims 1 to 7.
9. The pharmaceutical formulation of claim 8, further comprising one or more of a filler, a binder, a disintegrant, a coating agent, a salt, a lubricant; preferably, the filler is selected from one or more of lactose, sucrose, xylitol, sorbitol, calcium sulfate, mannitol, dextrin, starch, diatomite and kaolin; the adhesive is selected from one or more of pregelatinized starch and water-soluble resin; the disintegrant is selected from one or more of crospovidone, low-substituted hydroxypropyl cellulose, croscarmellose sodium, croscarmellose and sodium carboxymethyl starch; the coating agent is selected from one or more of acrylic resin, cellulose acetate phthalate, polyvinyl alcohol phthalate and cellulose acetate trimellitate; the salts are selected from one or more of ferrous sulfate, ferrous chloride, ferrous nitrate, ferrous phosphate, ferrous gluconate, zinc sulfate, zinc chloride, zinc nitrate, zinc phosphate and zinc gluconate; the lubricant is selected from one or more of magnesium stearate, superfine silica gel powder, talcum powder, calcium stearate, polyethylene glycol 6000 and methyl silicone oil.
10. Pharmaceutical formulation according to claim 8 or 9, wherein the pharmaceutical formulation is a solid formulation, preferably a tablet, capsule, granule, powder or drop pill.
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Citations (5)

* 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
US20060062847A1 (en) * 2004-09-15 2006-03-23 Basf Aktiengesellschaft Pharmaceutical dosage forms with impeded extractability of a sympathomimetic
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

Patent Citations (5)

* 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
US20060062847A1 (en) * 2004-09-15 2006-03-23 Basf Aktiengesellschaft Pharmaceutical dosage forms with impeded extractability of a sympathomimetic
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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