CN113197841A - Prochlorperazine suppository and preparation method thereof - Google Patents

Prochlorperazine suppository and preparation method thereof Download PDF

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Publication number
CN113197841A
CN113197841A CN202110549004.5A CN202110549004A CN113197841A CN 113197841 A CN113197841 A CN 113197841A CN 202110549004 A CN202110549004 A CN 202110549004A CN 113197841 A CN113197841 A CN 113197841A
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suppository
prochlorperazine
chitosan
polyethylene glycol
matrix
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徐成
葛雨
朱亚芳
刘馨忆
邢珍珍
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NANJING ZEHENG PHARMACEUTICAL SCIENCE & TECHNOLOGY CO LTD
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NANJING ZEHENG PHARMACEUTICAL SCIENCE & TECHNOLOGY CO LTD
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/02—Suppositories; Bougies; Bases therefor; Ovules
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/5415—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
    • 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
    • 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
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • 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
    • 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
    • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics

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  • Engineering & Computer Science (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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Abstract

The invention discloses a prochlorperazine suppository and a preparation method thereof, wherein the prochlorperazine suppository comprises the following components in percentage by mass: 1.25% of prochlorperazine, 3.0-8.0% of polyethylene glycol-chitosan, 8.0-12.0% of additive, 78.0-90.0% of suppository matrix, and 2g of suppository weight. According to the invention, only polyethylene glycol-chitosan is added as an auxiliary material, so that the biological adhesion of the suppository at the rectal temperature is improved, the degree of freedom in administration is improved, the release of prochlorperazine is promoted, and the curative effect and the compliance of the suppository are obviously superior to those of the existing commercially available prescription process.

Description

Prochlorperazine suppository and preparation method thereof
Technical Field
The invention relates to a suppository and a preparation method thereof, in particular to prochlorperazine suppository and a preparation method thereof.
Background
Cancer is one of the diseases that endanger the health of the residents of China. It accounts for 23.7% and 30% of the world in annual morbidity and mortality, respectively. The number of cancer attacks and deaths in China continues to increase due to aging, industrialization, and urbanization of the population, changes in lifestyle, and the like. Radiotherapy and chemotherapy are the main treatment means of cancer, but drugs can cause serious nausea and vomiting, and have negative effects on the life quality of patients and even the continuous treatment of the patients. Therefore, antiemetics occupy an important position in the field of tumor adjuvant therapy. In addition, in addition to the oral and intravenous routes, phenothiazines (promethazine and prochlorperazine) rectal suppositories may be selected for the treatment of nausea and vomiting during pregnancy when the pregnant woman who vomiting during pregnancy cannot tolerate oral medications.
The prochlorperazine is phenothiazine (structure formula shown in figure 1), and can antagonize dopamine D in brain Chemoreceptor Trigger Zone (CTZ)2Receptors with antiemetic, antipsychotic, antihistamine and anticholinergic activity prochlorperazine may also prevent chemotherapy-induced emesis. The prochlorperazine is prepared into a rectal administration preparation, so that the prochlorperazine can not lose activity due to the damage of gastrointestinal pH or enzyme, the first-pass effect of the liver can be effectively avoided, and the bioavailability is high. Is particularly suitable for treating patients who take chemotherapy and radiotherapy inconvenient to take orally, postoperative severe patients or patients who frequently vomit due to various reasons and can not take the medicine orally normally. However, the prochlorperazine suppository sold in the market is easy to flow out at the rectal temperature, has limited bioavailability and poor curative effect and compliance, and cannot meet the clinical requirements of patients.
Disclosure of Invention
The invention aims to provide a prochlorperazine suppository and a preparation method thereof, which overcome the defects of the prior art.
The prochlorperazine has a phenothiazine parent nucleus, and an S atom in a ring is a strong electron donor, so the prochlorperazine is easy to oxidize. The polyethylene glycol-chitosan has amphipathy, is easy to combine with negatively charged drugs, and can be combined with prochlorperazine to form a polymer to increase the water solubility of the prochlorperazine. In addition, rectal mucosa is composed of oligosaccharide chains of sialic acid, and a polyethylene glycol-chitosan-prochlorperazine polymer having a hydrophilic group can be firmly bound to the oligosaccharide chains thereof, thereby generating strong mucoadhesion. The inventor finds that after polyethylene glycol-chitosan is added as an additive, the bioadhesive property and the absorption property of the prochlorperazine suppository can be obviously improved. And the polyethylene glycol-chitosan is a chitosan derivative, has stronger biocompatibility with cells, and has low toxic and side effects and good safety.
The purpose of the invention is realized by the following technical scheme:
the prochlorperazine suppository is mainly prepared by mixing prochlorperazine, polyethylene glycol-chitosan and a suppository matrix, and the suppository comprises the following components in percentage by mass:
Figure BDA0003074646240000021
preferably, the suppository of the invention comprises the following components in percentage by mass:
Figure BDA0003074646240000022
wherein the additive is: one or more of glycerol, paraffin, propylene glycol, vitamin C, lanolin and triethanolamine, preferably glycerol, paraffin and propylene glycol.
Wherein the suppository matrix is fat-soluble matrix: one or more of semisynthetic hydrogenated palm kernel oil, semisynthetic hydrogenated coconut oil, glyceryl monostearate and cacao butter, preferably semisynthetic hydrogenated palm kernel oil and semisynthetic hydrogenated coconut oil are mixed as suppository matrix.
The invention further provides a preparation method of the suppository, and the hot melting method is selected.
The preparation method of the prochlorperazine suppository comprises the following steps:
(1) weighing raw materials and adjuvants according to the prescription.
(2) Melting suppository matrix in water bath, sequentially adding additive, polyethylene glycol-chitosan and prochlorperazine into the above melted matrix, dispersing uniformly, and keeping the temperature.
(3) Pouring into a mold, cooling, and demolding.
The prochlorperazine suppository has the advantages that: by only adding polyethylene glycol-chitosan as an auxiliary material, the biological adhesion of the suppository at the rectal temperature can be improved, the degree of freedom during administration can be improved, the release of prochlorperazine can be promoted, and the curative effect and the compliance of the suppository are obviously superior to those of the existing commercially available prescription process.
The following describes briefly the processes of selection of the additive and suppository base, screening of the dosage of polyethylene glycol-chitosan, etc. in the present invention.
Selection of additive and suppository base
The prochlorperazine suppository product is not available on the market at home, and part of auxiliary materials in the product available on the market at foreign countries cannot be purchased at home. Therefore, alternative auxiliary materials need to be found, and the additives are selected: one or more of glycerol, paraffin, propylene glycol, vitamin C, lanolin and triethanolamine; selecting a suppository matrix: semi-synthetic hydrogenated palm kernel oil, semi-synthetic hydrogenated coconut oil, glyceryl monostearate and cocoa butter. Weighing prochlorperazine and other adjuvants according to the prescription for use. Melting suppository matrix in water bath, sequentially adding additive, polyethylene glycol-chitosan and prochlorperazine into the above melted matrix, dispersing uniformly, and keeping the temperature. Pouring into a mold, cooling, and demolding.
The release characteristics of commercially available prochlorperazine suppositories and different self-developed suppositories were examined separately. The suppository was placed in the receptor chamber of a Franz diffusion cell (pore size 50mm), a pH 1.0 hydrochloric acid solution was added to the receptor chamber to the scale line, the rabbit rectum was sandwiched between the diffusion cell (receptor chamber) and the diffusion cell (receptor chamber), and the inner surface of the rabbit rectum was immersed in a pH 1.0 hydrochloric acid medium. The constant temperature circulating water keeps the constant temperature of 37 ℃ of the diffusion cell, the constant speed magnetic stirring rotating speed is 600rpm, the pH 1.0 hydrochloric acid solution is ensured to be uniformly distributed, 2ml of the solution is sampled every 30min, and the pH 1.0 hydrochloric acid solution with the same volume is supplemented, so that the drug release process of the transdermal preparation is objectively reflected.
The results are summarized in Table 1.
TABLE 1 selection of optimal additives and suppository base
Figure BDA0003074646240000041
The test result shows that the cumulative release degree of the glycerin, the paraffin and the propylene glycol are selected to be mixed as the suppository additive, any two or three of the semisynthetic hydrogenated palm kernel oil, the semisynthetic hydrogenated coconut oil and the glycerin monostearate are selected to be mixed as the suppository base, and the glycerin, the paraffin and the propylene glycol are commercially available prochlorperazine suppository.
Second, screening of dosage of polyethylene glycol-chitosan
The dosage of the polyethylene glycol-chitosan is smaller in the prescription, the dosage of the polyethylene glycol-chitosan has little influence on the release degree of the suppository, but the adhesion of the suppository to the rectum at 37 ℃ can be obviously influenced. The bioadhesion of the suppositories to the rabbit rectum was tested at 37 ℃ using a self-developed device (see FIG. 2) with different amounts of PEG-chitosan.
The plate to which the rectal tissue of the rabbit was fixed was attached at one end using a modified balance and at the other end to a small beaker containing a constant weight gain (peristaltic pump speed 10 rpm). The suppository is placed on a constant temperature heater at 37 deg.C, and is attached to rabbit rectal tissue for 3 min. The weight on the other end of the balance increased until the suppository was in contact with the rabbit rectal tissue. The adhesion was calculated from its separation time.
TABLE 2 screening of optimal PEG-Chitosan dosage
Figure BDA0003074646240000051
Test results show that the adhesion of the prochlorperazine suppository is obviously increased after the polyethylene glycol-chitosan is added as an auxiliary material. When the mass percentage of the added polyethylene glycol-chitosan is within 4.0-6.0%, the optimal rectal adhesion effect of the prochlorperazine suppository can be obtained.
Drawings
FIG. 1 is a structural formula of prochlorperazine.
FIG. 2 shows a self-grinding apparatus (a thermostatic heater, b prochlorperazine suppository, c rabbit rectal tissue, d modified balance, e beaker, f peristaltic pump).
Detailed Description
Example 1
Prochlorperazine 25mg
Polyethylene glycol-chitosan 80mg
Glycerin, paraffin wax and propylene glycol 200mg
Semi-synthetic hydrogenated palm kernel oil and semi-synthetic hydrogenated coconut oil 1695mg
Weighing raw materials and adjuvants according to the prescription. Melting suppository matrix in water bath, sequentially adding glycerol, paraffin, propylene glycol, polyethylene glycol-chitosan and prochlorperazine into melted semi-synthetic hydrogenated palm kernel oil and semi-synthetic hydrogenated coconut oil, dispersing uniformly, and keeping the temperature. Pouring into a mold, cooling, and demolding.
Example 2
Prochlorperazine 25mg
Polyethylene glycol-chitosan 100mg
Glycerin, paraffin wax and propylene glycol 200mg
Semi-synthetic hydrogenated palm kernel oil and semi-synthetic hydrogenated coconut oil 1675mg
Weighing raw materials and adjuvants according to the prescription. Melting suppository matrix in water bath, sequentially adding glycerol, paraffin, propylene glycol, polyethylene glycol-chitosan and prochlorperazine into melted semi-synthetic hydrogenated palm kernel oil and semi-synthetic hydrogenated coconut oil, dispersing uniformly, and keeping the temperature. Pouring into a mold, cooling, and demolding.
Example 3
Prochlorperazine 25mg
Polyethylene glycol-chitosan 120mg
Glycerin, paraffin wax and propylene glycol 200mg
Semi-synthetic hydrogenated palm kernel oil and semi-synthetic hydrogenated coconut oil 1655mg
Weighing raw materials and adjuvants according to the prescription. Melting suppository matrix in water bath, sequentially adding glycerol, paraffin, propylene glycol, polyethylene glycol-chitosan and prochlorperazine into melted semi-synthetic hydrogenated palm kernel oil and semi-synthetic hydrogenated coconut oil, dispersing uniformly, and keeping the temperature. Pouring into a mold, cooling, and demolding.

Claims (4)

1. The prochlorperazine suppository is prepared by mixing prochlorperazine, polyethylene glycol-chitosan and a suppository matrix, and comprises the following components in percentage by mass: prochlorperazine 1.25%, polyethylene glycol-chitosan 3.0-8.0%, additive 8.0-12.0%, suppository base 78.0-90.0%, each suppository weight is 2 g.
2. The prochlorperazine suppository according to claim 1, wherein the suppository comprises the following components in percentage by mass: prochlorperazine 1.25%, polyethylene glycol-chitosan 4.0-6.0%, additive 8.0-12.0%, suppository matrix 80.0-88.0%, each suppository weight is 2 g.
3. Prochlorperazine suppositories according to claims 1 and 2, wherein the additional agent is: one or more of glycerol, paraffin, propylene glycol, vitamin C, lanolin and triethanolamine, preferably glycerol, paraffin and propylene glycol.
4. The prochlorperazine suppository of claims 1, 2, wherein the suppository base is a fat-soluble base: one or more of semisynthetic hydrogenated palm kernel oil, semisynthetic hydrogenated coconut oil, glyceryl monostearate and cacao butter, preferably semisynthetic hydrogenated palm kernel oil and semisynthetic hydrogenated coconut oil are mixed as suppository matrix.
CN202110549004.5A 2021-05-20 2021-05-20 Prochlorperazine suppository and preparation method thereof Pending CN113197841A (en)

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