CN114533662A - Compound pholcodine oral solution and preparation method thereof - Google Patents

Compound pholcodine oral solution and preparation method thereof Download PDF

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Publication number
CN114533662A
CN114533662A CN202210061170.5A CN202210061170A CN114533662A CN 114533662 A CN114533662 A CN 114533662A CN 202210061170 A CN202210061170 A CN 202210061170A CN 114533662 A CN114533662 A CN 114533662A
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pholcodine
compound
oral solution
honey
polygala tenuifolia
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王琳琳
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Nanchang Lijian Pharmaceutical Co ltd
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Nanchang Lijian Pharmaceutical 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
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
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    • A61K31/09—Ethers or acetals having an ether linkage to aromatic ring nuclear carbon having two or more such linkages
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    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
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    • A61K31/535—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 oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
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    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
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    • A61K36/896—Liliaceae (Lily family), e.g. daylily, plantain lily, Hyacinth or narcissus
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    • 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
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    • A61K47/69—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6949—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
    • A61K47/6951—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2236/00—Isolation or extraction methods of medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicine
    • A61K2236/10—Preparation or pretreatment of starting material
    • A61K2236/15—Preparation or pretreatment of starting material involving mechanical treatment, e.g. chopping up, cutting or grinding
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2236/00—Isolation or extraction methods of medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicine
    • A61K2236/30—Extraction of the material
    • A61K2236/33—Extraction of the material involving extraction with hydrophilic solvents, e.g. lower alcohols, esters or ketones
    • A61K2236/331—Extraction of the material involving extraction with hydrophilic solvents, e.g. lower alcohols, esters or ketones using water, e.g. cold water, infusion, tea, steam distillation, decoction
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    • A61K2236/00—Isolation or extraction methods of medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicine
    • A61K2236/30—Extraction of the material
    • A61K2236/33—Extraction of the material involving extraction with hydrophilic solvents, e.g. lower alcohols, esters or ketones
    • A61K2236/333—Extraction of the material involving extraction with hydrophilic solvents, e.g. lower alcohols, esters or ketones using mixed solvents, e.g. 70% EtOH
    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2236/00—Isolation or extraction methods of medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicine
    • A61K2236/30—Extraction of the material
    • A61K2236/39—Complex extraction schemes, e.g. fractionation or repeated extraction steps
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    • A61K2236/00—Isolation or extraction methods of medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicine
    • A61K2236/50—Methods involving additional extraction steps
    • A61K2236/51—Concentration or drying of the extract, e.g. Lyophilisation, freeze-drying or spray-drying
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    • A61K2236/00—Isolation or extraction methods of medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicine
    • A61K2236/50—Methods involving additional extraction steps
    • A61K2236/53—Liquid-solid separation, e.g. centrifugation, sedimentation or crystallization

Abstract

The invention discloses a compound pholcodine oral solution and a preparation method thereof, the preparation method can effectively embed pseudoephedrine hydrochloride and slow down the adverse reaction of dizziness and somnolence of the compound pholcodine oral solution; the polygala tenuifolia fluid extract prepared by the invention is beneficial to reducing the stimulation of the compound pholcodine oral solution to the gastrointestinal tract and improving the administration compliance of the compound pholcodine oral solution.

Description

Compound pholcodine oral solution and preparation method thereof
Technical Field
The invention relates to a compound pholcodine oral solution and a preparation method thereof.
Background
The compound pholcodine oral solution mainly comprises pholcodine, triprolidine hydrochloride, pseudoephedrine hydrochloride and guaifenesin, and a certain amount of herba Alii Fistulosi fluid extract and cortex et radix Polygalae fluid extract, and is mainly used for treating cough caused by common cold, influenza, throat and bronchial irritation, excessive phlegm cough, dry cough, nasal obstruction and sore throat. Wherein the pholcodine is a central antitussive; triprolidine hydrochloride is an antihistamine and can reduce edema of respiratory tract; pseudoephedrine hydrochloride can resist nasal mucosa congestion and eustachian tube congestion; guaifenesin can dilate bronchus to reduce the viscosity of airway secretion, and has the function of reducing phlegm; the herba Alii Fistulosi fluid extract has expectorant and antitussive effects; the cortex et radix Polygalae fluid extract has effects of concentrating mind and eliminating phlegm.
However, in the prior art, the compound pholcodine oral solution is easy to cause dizziness and sleepiness of patients, stimulates gastrointestinal tracts to cause discomfort symptoms such as regurgitation and heartburn.
Disclosure of Invention
The invention develops a compound pholcodine oral solution and a preparation method thereof, which improves the formula and the preparation method of the compound pholcodine oral solution and effectively reduces adverse reactions.
The compound pholcodine oral solution comprises the following medicinal components in parts by volume: 1mg of pholcodine, 0.12mg of triprolidine hydrochloride, 3.0mg of pseudoephedrine hydrochloride, 10.0mg of guaifenesin, 0.001mL of shallot fluid extract and 0.001mL of polygala tenuifolia fluid extract.
Further, the compound pholcodine oral solution also comprises other additives: such as sweeteners, preservatives, flavoring agents, tints, flavorings, pH adjusters, and the like. The sweetener comprises sucrose, aspartame, etc.; the preservative is preferably potassium sorbate; flavoring agents include citric acid, menthol, etc., wherein citric acid is also used to adjust the pH; the toner comprises amaranth pigment, carmine pigment, etc.; the flavoring agent comprises alcohol, essence, etc.
The preparation method of the compound pholcodine oral solution comprises the following steps:
(1) adding pseudoephedrine hydrochloride into purified water with the mass 3-5 times that of the pseudoephedrine hydrochloride, uniformly stirring, adding mixed powder of beta-cyclodextrin and gamma-cyclodextrin with the mass ratio of 1: 2-3, the mass of which is equal to that of the pseudoephedrine hydrochloride, uniformly homogenizing and dispersing, adding a mixture of menthol and edible alcohol with the mass of 2% of the pseudoephedrine hydrochloride and the mass of which is 1:1, and homogenizing to obtain sol;
(2) and (3) adding other medicinal components according to the proportion, after the dissolution is finished, adding the sol prepared in the step (1), dispersing, and adjusting the pH to 2.5-3.5 to obtain the compound pholcodine oral solution.
Further, the preparation method of the polygala tenuifolia fluid extract comprises the following steps:
(1) slicing 1kg of polygala tenuifolia, adding refined honey of 1/4-1/3 mass percent of polygala tenuifolia and a mixed enzyme preparation of cellulase and hemicellulase in a mass ratio of 3-5: 1 of polygala tenuifolia, uniformly stirring, and stewing for 10-12 h at room temperature; then stir-frying the slices with slow fire until the surface is slightly yellow to obtain honey-processed polygala tenuifolia slices;
(2) slicing honey polygala tenuifolia into 50-100-mesh powder, soaking the honey polygala tenuifolia into purified water with the mass multiple of 2-3 times and the temperature of 40-50 ℃ for 1-2 hours, removing the purified water, adding ethanol with the mass fraction of 40%, soaking the honey polygala tenuifolia for 2-3 hours, slowly percolating the honey polygala tenuifolia at the speed of 1-3 mL per minute, and collecting primary percolate A with the volume of 200-300 mL; then soaking the filter cake in 50% ethanol for 2-3 h, and collecting 200-300 mL of a second percolate B by the same process; similarly, continuously collecting 200-300 mL of a third percolate C by using ethanol with the mass fraction of 60%, and finally collecting 200-300 mL of a final percolate D by using ethanol with the mass fraction of 70%;
(3) mixing the percolates A, B, C, D, distilling at 50-60 deg.C under reduced pressure, concentrating to obtain soft extract, adding ammonia water, adjusting to alkalescence, diluting with 60% ethanol to 1000mL, standing, clarifying, and filtering to obtain cortex et radix Polygalae fluid extract.
The preparation method of the refined honey comprises the following steps: putting the raw honey into a copper pot, heating with slow fire until the honey is boiled, taking out the foam and the floating wax, filtering to remove dead bees and impurities, and adding purified water with the honey quality of 1/4-1/3 to obtain the honey.
The vacuum degree of the reduced pressure distillation is-0.08 to-0.09 MPa.
The invention has the advantages that:
1. the preparation method can effectively embed the pseudoephedrine hydrochloride and slow down the adverse reaction of dizziness and somnolence of the compound pholcodine oral solution;
2. the polygala tenuifolia fluid extract prepared by the invention is beneficial to reducing the stimulation of the compound pholcodine oral solution to the gastrointestinal tract and improving the administration compliance of the compound pholcodine oral solution.
Detailed Description
Example 1
The compound pholcodine oral solution comprises the following medicinal components in parts by volume: 1mg of pholcodine, 0.12mg of triprolidine hydrochloride, 3.0mg of pseudoephedrine hydrochloride, 10.0mg of guaifenesin, 0.001mL of shallot fluid extract and 0.001mL of polygala tenuifolia fluid extract.
The preparation method of the compound pholcodine oral solution comprises the following steps:
(1) adding pseudoephedrine hydrochloride into purified water with the mass 3 times that of the pseudoephedrine hydrochloride, stirring uniformly, adding mixed powder of beta-cyclodextrin and gamma-cyclodextrin with the mass ratio of 1:2, which is the same as that of the pseudoephedrine hydrochloride, homogenizing and dispersing uniformly, adding a mixture of menthol and edible alcohol with the mass 2% of the pseudoephedrine hydrochloride and 1:1, and homogenizing to obtain sol;
(2) adding other medicinal components according to the proportion, after the dissolution is finished, adding the sol prepared in the step (1), dispersing, and adding citric acid to adjust the pH value to 2.5 to obtain the compound pholcodine oral solution.
The preparation method of the polygala tenuifolia fluid extract comprises the following steps:
(1) slicing 1kg of polygala tenuifolia, adding refined honey 1/4 mass of polygala tenuifolia and a mixed enzyme preparation with the mass ratio of cellulase to hemicellulase being 5:1 of polygala tenuifolia, uniformly stirring, and stewing for 12 hours at room temperature; then stir-frying the slices with slow fire until the surface is yellowish to obtain honey-processed polygala tenuifolia slices;
(2) slicing honey-processed polygala tenuifolia into 50-mesh powder, soaking the honey-processed polygala tenuifolia into purified water with the mass multiple of 2 times and the temperature of 50 ℃ for 1 hour, removing the purified water, then adding ethanol with the mass fraction of 40%, soaking the honey-processed polygala tenuifolia for 2 hours, slowly percolating the honey-processed polygala tenuifolia at the speed of 1mL per minute, and collecting 300mL of primary percolate A; then soaking the filter cake in 50% ethanol for 2h, and collecting 300mL of second percolate B by the same process; similarly, continuously collecting 300mL of the third percolate C with the ethanol with the mass fraction of 60%, and finally collecting 300mL of the final percolate D with the ethanol with the mass fraction of 70%;
(3) mixing percolates A, B, C, D, distilling at 60 deg.C under vacuum degree of-0.08 MPa, concentrating into soft extract, adding ammonia water, adjusting to alkalescence, diluting with 60% ethanol to 1000mL, standing, clarifying, and filtering to obtain cortex et radix Polygalae fluid extract.
The preparation method of the refined honey comprises the following steps: placing the crude honey in a copper pot, heating with slow fire until the honey is boiled, taking out the foam and the floating wax, filtering to remove dead bees and impurities, and adding purified water with the quality of 1/4 of the honey to obtain the honey.
Example 2
The compound pholcodine oral solution comprises the following medicinal components in parts by volume: 1mg of pholcodine, 0.12mg of triprolidine hydrochloride, 3.0mg of pseudoephedrine hydrochloride, 10.0mg of guaifenesin, 0.001mL of shallot fluid extract and 0.001mL of polygala tenuifolia fluid extract.
The preparation method of the compound pholcodine oral solution comprises the following steps:
(1) adding pseudoephedrine hydrochloride into purified water with the mass 4 times that of the pseudoephedrine hydrochloride, stirring uniformly, adding mixed powder of beta-cyclodextrin and gamma-cyclodextrin with the mass ratio of 1:3, which is the same as the pseudoephedrine hydrochloride, homogenizing and dispersing uniformly, adding a mixture of menthol and edible alcohol with the mass 2% of the pseudoephedrine hydrochloride and 1:1, and homogenizing to obtain sol;
(2) adding other medicinal components according to the proportion, after the dissolution is finished, adding the sol prepared in the step (1), dispersing, and adding citric acid to adjust the pH value to 3.0 to obtain the compound pholcodine oral solution.
The preparation method of the polygala tenuifolia fluid extract comprises the following steps:
(1) slicing 1kg of polygala tenuifolia, adding refined honey 1/3 mass of polygala tenuifolia and a mixed enzyme preparation with the mass ratio of cellulase to hemicellulase being 4:1 of polygala tenuifolia, uniformly stirring, and stewing for 11h at room temperature; then stir-frying the slices with slow fire until the surface is yellowish to obtain honey-processed polygala tenuifolia slices;
(2) slicing honey-processed polygala tenuifolia into 70-mesh powder, soaking the honey-processed polygala tenuifolia into purified water at 45 ℃ by mass times of 2.5 times for 1.2 hours, removing the purified water, adding ethanol with the mass fraction of 40%, soaking the honey-processed polygala tenuifolia for 2.5 hours, slowly percolating the honey-processed polygala tenuifolia at the speed of 2mL per minute, and collecting primary percolate A250 mL; then soaking the raw materials in 50% ethanol for 2.5h, and collecting a second percolate B250mL by the same process; similarly, continuously collecting the third percolate C250 mL by using ethanol with the mass fraction of 60%, and finally collecting the final percolate D250 mL by using ethanol with the mass fraction of 70%;
(3) mixing percolates A, B, C, D, distilling at 55 deg.C under vacuum degree of-0.09 MPa, concentrating into soft extract, adding ammonia water, adjusting to alkalescence, diluting with 60% ethanol to 1000mL, standing, clarifying, and filtering to obtain cortex et radix Polygalae fluid extract.
The preparation method of the refined honey comprises the following steps: placing the crude honey in a copper pot, heating with slow fire until the honey is boiled, taking out the foam and the floating wax, filtering to remove dead bees and impurities, and adding purified water with the quality of 1/3 of the honey to obtain the honey.
Example 3
The compound pholcodine oral solution comprises the following medicinal components in parts by volume: 1mg of pholcodine, 0.12mg of triprolidine hydrochloride, 3.0mg of pseudoephedrine hydrochloride, 10.0mg of guaifenesin, 0.001mL of shallot fluid extract and 0.001mL of polygala tenuifolia fluid extract.
The preparation method of the compound pholcodine oral solution comprises the following steps:
(1) adding pseudoephedrine hydrochloride into purified water with the mass 5 times that of the pseudoephedrine hydrochloride, stirring uniformly, adding mixed powder of beta-cyclodextrin and gamma-cyclodextrin with the mass ratio of 1:3, which is the same as the pseudoephedrine hydrochloride, homogenizing and dispersing uniformly, adding a mixture of menthol and edible alcohol with the mass 2% of the pseudoephedrine hydrochloride and 1:1, and homogenizing to obtain sol;
(2) adding other medicinal components according to the proportion, after the dissolution is finished, adding the sol prepared in the step (1), dispersing, and adding citric acid to adjust the pH value to 3.5 to obtain the compound pholcodine oral solution.
The preparation method of the polygala tenuifolia fluid extract comprises the following steps:
(1) slicing 1kg of polygala tenuifolia, adding refined honey 1/3 mass of polygala tenuifolia and a mixed enzyme preparation with the mass ratio of cellulase to hemicellulase being 3:1 of polygala tenuifolia, uniformly stirring, and stewing for 10 hours at room temperature; then stir-frying the slices with slow fire until the surface is yellowish to obtain honey-processed polygala tenuifolia slices;
(2) slicing honey-processed polygala tenuifolia into 100-mesh powder, soaking the powder in purified water with the mass multiple of 3 times and the temperature of 40 ℃ for 2 hours, removing the purified water, then adding ethanol with the mass fraction of 40%, soaking the powder for 3 hours, slowly percolating the solution at the speed of 3mL per minute, and collecting 200mL of primary percolate A; then soaking the filter cake in 50% ethanol for 3h, and collecting 200mL of a second percolate B by the same process; similarly, continuously collecting the third percolate C200 mL by using ethanol with the mass fraction of 60%, and finally collecting the final percolate D200 mL by using ethanol with the mass fraction of 70%;
(3) mixing percolates A, B, C, D, distilling at 50 deg.C under vacuum degree of-0.09 MPa, concentrating into soft extract, adding ammonia water, adjusting to alkalescence, diluting with 60% ethanol to 1000mL, standing, clarifying, and filtering to obtain cortex et radix Polygalae fluid extract.
The preparation method of the refined honey comprises the following steps: placing the crude honey in a copper pot, heating with slow fire until the honey is boiled, taking out the foam and the floating wax, filtering to remove dead bees and impurities, and adding purified water with the quality of 1/3 of the honey to obtain the honey.
Example 4
The compound pholcodine oral solution comprises the following medicinal components in parts by volume: 1mg of pholcodine, 0.12mg of triprolidine hydrochloride, 3.0mg of pseudoephedrine hydrochloride, 10.0mg of guaifenesin, 0.001mL of shallot fluid extract and 0.001mL of polygala tenuifolia fluid extract.
The preparation method of the compound pholcodine oral solution comprises the following steps:
(1) adding pseudoephedrine hydrochloride into purified water with the mass 2.2 times that of the pseudoephedrine hydrochloride, stirring uniformly, adding mixed powder of beta-cyclodextrin and gamma-cyclodextrin with the mass ratio of 1:4 which is the same as that of the pseudoephedrine hydrochloride, homogenizing and dispersing uniformly, adding a mixture of menthol with the mass 2% of the pseudoephedrine hydrochloride and 1:1 edible alcohol, and homogenizing to obtain sol;
(2) adding other medicinal components according to the proportion, after the dissolution is finished, adding the sol prepared in the step (1), dispersing, and adding citric acid to adjust the pH value to 4.0 to obtain the compound pholcodine oral solution.
The preparation method of the polygala tenuifolia fluid extract comprises the following steps:
(1) slicing 1kg of polygala tenuifolia, adding refined honey 1/2 mass of polygala tenuifolia and a mixed enzyme preparation with the mass ratio of cellulase to hemicellulase being 6:1 of polygala tenuifolia, uniformly stirring, and stewing for 9 hours at room temperature; then stir-frying the slices with slow fire until the surface is yellowish to obtain honey-processed polygala tenuifolia slices;
(2) slicing honey-processed polygala tenuifolia into 40-mesh powder, soaking the powder in purified water with the mass multiple of 4 times and the temperature of 35 ℃ for 3 hours, removing the purified water, then adding ethanol with the mass fraction of 40%, soaking the powder for 1.5 hours, slowly percolating the solution at the speed of 0.6mL per minute, and collecting 180mL of primary percolate A; then soaking the raw materials in 50% ethanol for 1.5h, and collecting a second percolate B180mL by the same process; similarly, continuously collecting 180mL of the third percolate with ethanol with the mass fraction of 60%, and finally collecting 180mL of the final percolate with ethanol with the mass fraction of 70%;
(3) mixing percolates A, B, C, D, distilling at 48 deg.C under vacuum degree of-0.095 MPa, concentrating into soft extract, adding ammonia water, adjusting to alkalescence, diluting with 60% ethanol to 1000mL, standing, clarifying, and filtering to obtain cortex et radix Polygalae fluid extract.
The preparation method of the refined honey comprises the following steps: placing the crude honey in a copper pot, heating with slow fire until the honey is boiled, taking out the foam and the floating wax, filtering to remove dead bees and impurities, and adding purified water with the quality of 1/2 of the honey to obtain the honey.
Example 5
The compound pholcodine oral solution comprises the following medicinal components in parts by volume: 1mg of pholcodine, 0.12mg of triprolidine hydrochloride, 3.0mg of pseudoephedrine hydrochloride, 10.0mg of guaifenesin, 0.001mL of shallot fluid extract and 0.001mL of polygala tenuifolia fluid extract.
The preparation method of the compound pholcodine oral solution comprises the following steps:
(1) adding pseudoephedrine hydrochloride into purified water with the mass 6 times that of the pseudoephedrine hydrochloride, stirring uniformly, adding mixed powder of beta-cyclodextrin and gamma-cyclodextrin with the mass ratio of 1:1, which is the same as the pseudoephedrine hydrochloride, homogenizing and dispersing uniformly, adding a mixture of menthol and edible alcohol with the mass 2% of the pseudoephedrine hydrochloride and 1:1, and homogenizing to obtain sol;
(2) adding other medicinal components according to the proportion, after the dissolution is finished, adding the sol prepared in the step (1), dispersing, and adding citric acid to adjust the pH value to 2.0 to obtain the compound pholcodine oral solution.
The preparation method of the polygala tenuifolia fluid extract comprises the following steps:
(1) slicing 1kg of polygala tenuifolia, adding refined honey 1/5 mass of polygala tenuifolia and a mixed enzyme preparation with the mass ratio of cellulase to hemicellulase being 2:1 of polygala tenuifolia, uniformly stirring, and stewing for 14 hours at room temperature; then stir-frying the slices with slow fire until the surface is yellowish to obtain honey-processed polygala tenuifolia slices;
(2) slicing honey-processed polygala tenuifolia into 120-mesh powder, soaking the honey-processed polygala tenuifolia into 55-DEG purified water with the mass multiple of 1.8 times for 0.9h, then removing the purified water, adding ethanol with the mass fraction of 40%, soaking the honey-processed polygala tenuifolia for 3.5h, slowly percolating the honey-processed polygala tenuifolia at the speed of 4mL per minute, and collecting 400mL of primary percolate A; then soaking the raw materials in 50% ethanol for 3.5h, and collecting a second percolate B400mL by the same process; similarly, continuously collecting the third percolate C400 mL by using ethanol with the mass fraction of 60%, and finally collecting the final percolate D400 mL by using ethanol with the mass fraction of 70%;
(3) mixing percolates A, B, C, D, distilling at 65 deg.C under vacuum degree of-0.07 MPa, concentrating into soft extract, adding ammonia water, adjusting to alkalescence, diluting with 60% ethanol to 1000mL, standing, clarifying, and filtering to obtain cortex et radix Polygalae fluid extract.
The preparation method of the refined honey comprises the following steps: placing the crude honey in a copper pot, heating with slow fire until the honey is boiled, taking out the foam and the floating wax, filtering to remove dead bees and impurities, and adding purified water with the quality of 1/5 of the honey to obtain the honey.
Comparative example 1
A compound Folcodine oral solution, wherein the preparation method of cortex et radix Polygalae fluid extract comprises: taking 1kg of polygala tenuifolia powder of 70 meshes, according to a percolation method (appendix I O) under the items of fluid extract and extract, using 60% ethanol as a solvent, soaking for 24 hours, slowly percolating at the speed of 2ml per minute, collecting 850ml of primary percolate, preserving in another container, continuing percolating until the effective components are completely percolated, collecting continuous percolate, concentrating to be thick paste at 60 ℃, adding the primary filtrate, mixing, dropwise adding a proper amount of concentrated ammonia test solution to make the concentrated ammonia test solution slightly alkaline, diluting with 60% ethanol to 1000ml, standing, clarifying, and filtering to obtain polygala tenuifolia fluid extract; the rest is the same as example 2.
Comparative example 2
A compound Folcodine oral liquid is prepared by the method (1) without adding refined honey, and the rest is the same as example 2.
Comparative example 3
A compound Folcodine oral liquid is prepared by the method (1) without adding mixed enzyme preparation, and the rest is the same as example 2.
Comparative example 4
A compound Folcodine oral solution is prepared by using cellulase as enzyme preparation in step (1) of radix Polygalae fluid extract preparation method, and the rest is the same as example 2.
Comparative example 5
A compound Folduding oral liquid is prepared by the method (2) without soaking radix Polygalae fluid extract in purified water, and the rest is the same as example 2.
Comparative example 6
A compound Folcodine oral liquid is prepared by soaking cortex et radix Polygalae fluid extract in 60% ethanol for 10 hr in step (2), and collecting 1000mL primary percolate at a speed of 2 mL/min, the rest is the same as example 2.
Comparative example 7
The preparation method of the compound pholcodine oral solution is the same as that of the embodiment 2, and the preparation method comprises the steps of dissolving all the raw materials in purified water, and then adding citric acid to adjust the pH value to 3.0, so as to obtain the compound pholcodine oral solution.
Comparative example 8
The preparation method of the compound pholcodine oral solution is the same as that of the example 2 except that the mixed powder of beta-cyclodextrin and gamma-cyclodextrin in the mass ratio of 1:3 is not added in the step (1).
Comparative example 9
A compound Folcodine oral solution is prepared by adding only an equal amount of beta-cyclodextrin in step (1), and the rest is the same as in example 2.
Comparative example 10
A compound Folcodine oral solution is prepared by the method (1) without adding a mixture of menthol and edible alcohol 1:1, and the rest is the same as example 2.
Comparative example 11
The preparation method of the compound pholcodine oral solution is the same as that of the comparative example 1, and the preparation method comprises the steps of dissolving all the raw materials in purified water, and then adding citric acid to adjust the pH value to 3.0, so as to obtain the compound pholcodine oral solution.
Detection and analysis:
1. drug efficacy testing
(1) Ammonia water induced cough method for mice
170 healthy mice with the weight of 20-25 g are taken and randomly divided into 17 groups according to the weight, wherein each group comprises 10 mice, and the male and female groups are half of each other and correspond to the examples and the comparative examples, and the other group is a blank control group. The blank control group is infused with 20mL/kg of normal saline, and the other groups are infused with 20mL/kg of compound pholcodine oral solution prepared in the corresponding embodiment or the corresponding comparative example; continuously taking 3 days, 1 time every day, placing the mice in a closed glass cover after the last administration for 1 hour, spraying 25% concentrated ammonia water for 20 seconds by using an ultrasonic atomizer, immediately taking out the mice after the spraying is finished, taking contraction and expansion of abdominal muscles of the mice as cough action indicators, and recording the cough times and the latency of the mice within 3 minutes:
(2) mouse phenol red phlegm eliminating test
170 healthy mice with the weight of 20-25 g are taken and randomly divided into 17 groups according to the weight, wherein each group comprises 10 mice, and the male and female groups are half of each other and correspond to the examples and the comparative examples, and the other group is a blank control group. The blank control group is infused with normal saline with 20mL/kg, and the other groups are infused with the compound pholcodine oral solution prepared in the corresponding embodiment or the comparative example with 20 mL/kg; continuously taking 3 days, taking 1 time per day, and fasting for 24 hours before experiment without water supply; 30 minutes after the last administration, 5% phenol red solution is injected into abdominal cavity for 500g/kg, the mouse is killed after 30 minutes, tissues around the trachea are stripped, a section of trachea from the lower part of the thyroid cartilage to the branch part of the trachea is cut off, the trachea is placed into a test tube containing 1mL of physiological saline, 0.1mL of 1mol/L sodium hydroxide solution is added into each sample solution, the sample solution is soaked for 24 hours, the supernatant is taken, the A value is measured at the wavelength of 546nm, and then the absorbance is converted into the phenol red content according to a phenol red standard curve, so that the phenol red excretion of the mouse is obtained.
Test specimen Cough incubation(s) Cough frequency within 3min (times) Phenol Red excretion (μ g/mL)
Blank control group 61.6 29.4 0.71
Example 1 97.1 4.2 3.16
Example 2 98.9 4.0 3.22
Example 3 97.3 4.3 3.15
Example 4 87.7 7.3 2.85
Example 5 88.0 7.0 2.81
Comparative example 1 90.1 5.7 2.88
Comparative example 2 91.3 5.5 2.95
Comparative example 3 90.6 5.9 2.93
Comparative example 4 92.8 5.4 2.98
Comparative example 5 95.7 4.8 3.06
Comparative example 6 91.5 5.4 2.94
Comparative example 7 93.3 5.2 3.01
Comparative example 8 91.9 5.5 2.92
Comparative example 9 91.5 5.9 2.89
Comparative example 10 86.6 6.8 2.80
Comparative example 11 86.1 7.5 2.77
2. And (3) clinical trials:
160 children with mild cold of 6 years old and 160 children with severe cold of 6 years old are selected in the flu season and randomly divided into 16 groups respectively, and the groups correspond to the examples and the comparative examples; the medicine is taken once in the morning, in the middle of the day and at night, the dosage is 5ml, the number of people who feel dizzy and feel uncomfortable in the gastrointestinal tract after the medicine is taken is observed and recorded on the first day, and the proportion of the dizziness to the sleep and the proportion of the discomfort in the gastrointestinal tract are calculated; and the time of healing (days) was recorded and averaged to give the time of healing (days).
Figure BDA0003478409970000121
And finally: the above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents, improvements and the like that are within the spirit and principle of the present invention are intended to be included in the scope of the present invention.

Claims (10)

1. A compound pholcodine oral solution is characterized in that: the compound pholcodine oral solution comprises the following medicinal components in parts by weight per milliliter: 1mg of pholcodine, 0.12mg of triprolidine hydrochloride, 3.0mg of pseudoephedrine hydrochloride, 10.0mg of guaifenesin, 0.001mL of shallot fluid extract and 0.001mL of polygala tenuifolia fluid extract.
2. The compound pholcodine oral solution of claim 1, wherein: the compound pholcodine oral solution also comprises a sweetening agent.
3. The compound pholcodine oral solution of claim 1, wherein: the compound pholcodine oral solution also comprises a preservative.
4. The compound pholcodine oral solution of claim 1, wherein: the compound pholcodine oral solution also comprises a flavoring agent or a pH regulator.
5. The compound pholcodine oral solution of claim 1, wherein: the compound pholcodine oral solution also comprises toner.
6. The compound pholcodine oral solution of claim 1, wherein: the compound pholcodine oral solution also comprises a flavoring agent.
7. The compound pholcodine oral solution of claim 1, wherein: the preparation method of the compound pholcodine oral solution comprises the following steps:
(1) adding pseudoephedrine hydrochloride into purified water with the mass 3-5 times that of the pseudoephedrine hydrochloride, uniformly stirring, adding mixed powder of beta-cyclodextrin and gamma-cyclodextrin with the mass ratio of 1: 2-3, the mass of which is equal to that of the pseudoephedrine hydrochloride, uniformly homogenizing and dispersing, adding a mixture of menthol and edible alcohol with the mass of 2% of the pseudoephedrine hydrochloride and the mass of which is 1:1, and homogenizing to obtain sol;
(2) and (3) adding other medicinal components according to the proportion, after the dissolution is finished, adding the sol prepared in the step (1), dispersing, and adjusting the pH to 2.5-3.5 to obtain the compound pholcodine oral solution.
8. The compound pholcodine oral solution of claim 1, wherein: the preparation method of the polygala tenuifolia fluid extract comprises the following steps:
(1) slicing 1kg of polygala tenuifolia, adding refined honey of 1/4-1/3 mass percent of polygala tenuifolia and a mixed enzyme preparation of cellulase and hemicellulase in a mass ratio of 3-5: 1 of polygala tenuifolia, uniformly stirring, and stewing for 10-12 h at room temperature; then stir-frying the slices with slow fire until the surface is yellowish to obtain honey-processed polygala tenuifolia slices;
(2) slicing honey polygala tenuifolia into 50-100-mesh powder, soaking the honey polygala tenuifolia into purified water with the mass multiple of 2-3 times and the temperature of 40-50 ℃ for 1-2 hours, removing the purified water, adding ethanol with the mass fraction of 40%, soaking the honey polygala tenuifolia for 2-3 hours, slowly percolating the honey polygala tenuifolia at the speed of 1-3 mL per minute, and collecting primary percolate A with the volume of 200-300 mL; then soaking the filter cake in 50% ethanol for 2-3 h, and collecting 200-300 mL of a second percolate B by the same process; similarly, continuously collecting 200-300 mL of a third percolate C by using ethanol with the mass fraction of 60%, and finally collecting 200-300 mL of a final percolate D by using ethanol with the mass fraction of 70%;
(3) mixing the percolates A, B, C, D, distilling at 50-60 deg.C under reduced pressure, concentrating to obtain soft extract, adding ammonia water, adjusting to alkalescence, diluting with 60% ethanol to 1000mL, standing, clarifying, and filtering to obtain cortex et radix Polygalae fluid extract.
9. The compound pholcodine oral solution of claim 8, wherein: the preparation method of the refined honey comprises the following steps: putting the raw honey into a copper pot, heating with slow fire until the honey is boiled, taking out the foam and the floating wax, filtering to remove dead bees and impurities, and adding purified water with the honey quality of 1/4-1/3 to obtain the honey.
10. The compound pholcodine oral solution of claim 8, wherein: the vacuum degree of the reduced pressure distillation is-0.08 to-0.09 MPa.
CN202210061170.5A 2022-01-19 2022-01-19 Compound pholcodine oral solution and preparation method thereof Pending CN114533662A (en)

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