CN110934833A - Compound paracetamol and chlorphenamine maleate granules - Google Patents
Compound paracetamol and chlorphenamine maleate granules Download PDFInfo
- Publication number
- CN110934833A CN110934833A CN201911300698.8A CN201911300698A CN110934833A CN 110934833 A CN110934833 A CN 110934833A CN 201911300698 A CN201911300698 A CN 201911300698A CN 110934833 A CN110934833 A CN 110934833A
- Authority
- CN
- China
- Prior art keywords
- curcumin
- compound
- chlorphenamine maleate
- monophosphate
- paracetamol
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Images
Classifications
-
- 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
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
- A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
-
- 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
- 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
- A61K31/435—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
- A61K31/4402—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 2, e.g. pheniramine, bisacodyl
-
- 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
- A61K31/66—Phosphorus compounds
- A61K31/661—Phosphorus acids or esters thereof not having P—C bonds, e.g. fosfosal, dichlorvos, malathion or mevinphos
- A61K31/6615—Compounds having two or more esterified phosphorus acid groups, e.g. inositol triphosphate, phytic acid
-
- 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
- A61K47/50—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
- 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
-
- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1617—Organic compounds, e.g. phospholipids, fats
- A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Virology (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Molecular Biology (AREA)
- Pain & Pain Management (AREA)
- Pulmonology (AREA)
- Oncology (AREA)
- Communicable Diseases (AREA)
- Emergency Medicine (AREA)
- Rheumatology (AREA)
- Biophysics (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention relates to the technical field of medicines, in particular to compound paracetamol and chlorphenamine maleate granules, which are characterized by comprising main functional components of acetaminophen, chlorphenamine maleate and methyl ephedrine hydrochloride, synergistic components of curcumin type inclusion compounds and powdered sugar, wherein the curcumin type inclusion compounds are prepared by inclusion by taking hydroxypropyl- β -cyclodextrin mixtures with different substitution degrees as main bodies and taking curcumin monophosphate and/or salts thereof as objects.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to compound paracetamol and chlorphenamine maleate granules.
Background
The main components of the traditional compound paracetamol granules are acetaminophen and chlorpheniramine maleate, wherein acetaminophen is acetanilide antipyretic analgesics, also called paracetamol (paracetamol), is an in vivo metabolite of phenacetin, belongs to anilines, can reduce synthesis and release of prostaglandin PGE1 by inhibiting hypothalamic temperature and regulating central prostaglandin synthetase, causes peripheral vasodilation and sweating to achieve antipyretic effect, has similar antipyretic effect strength to aspirin but has no obvious anti-inflammatory effect, has the effect of improving pain threshold by inhibiting synthesis and release of prostaglandin PGE1, bradykinin and histamine and the like, belongs to peripheral analgesics which have weaker analgesic effect than aspirin and effective only on mild and moderate pain, and chlorpheniramine maleate is an H1 receptor antagonist which has a hydrocarbon amine chemical structure, can mainly competitively block histamine H1 receptor on allergic target cells, cannot bind with H1 receptor, thereby inhibiting the reaction of histamine which causes excessive histamine, and further has the effect of inhibiting the central hyperalgesia of the central chlorpheniramine maleate and the central hyperalgesia of children, and the central hyperalgesia of the hyperthyroidism.
The above background disclosure is only for the purpose of assisting understanding of the inventive concept and technical solutions of the present invention, and does not necessarily belong to the prior art of the present patent application, and should not be used for evaluating the novelty and inventive step of the present application in the case that there is no clear evidence that the above content is disclosed at the filing date of the present patent application.
Disclosure of Invention
The invention aims to provide compound paracetamol and chlorphenamine maleate granules, which can protect the quality stability of ultra-low concentration chlorphenamine maleate and methamphetamine hydrochloride, thereby ensuring the stable quality and high efficiency of a compound paracetamol and chlorphenamine maleate granule composition, and avoiding the problems of side effect, adverse reaction and excessive high concentration methamphetamine hydrochloride of a main drug with higher concentration and the problem of reduced quality stability of drug effect of the main drug with lower concentration.
The technical scheme adopted by the invention for realizing the purpose is as follows:
[1] a compound paracetamol and chlorpheniramine maleate particle comprising:
the main effective components are acetaminophen, chlorphenamine maleate and methyl ephedrine hydrochloride;
synergistic component, which is curcumin compound; and
powdered sugar;
the curcumin complex is prepared by taking hydroxypropyl- β -cyclodextrin (HP- β -CD) mixtures with different Degrees of Substitution (DS) as a main body and taking curcumin monophosphate and/or salts thereof as a guest through inclusion, and is specifically shown in figure 2.
The application provides compound paracetamol and chlorphenamine maleate granules, which specifically take chlorphenamine maleate, acetaminophen and methyl ephedrine hydrochloride as main functional components, take hydroxypropyl- β -cyclodextrin mixture with different substitution degrees to include curcumin monophosphate and/or curcumin-hydroxypropyl- β -cyclodextrin (Cur-HP- β -CD) inclusion compound formed by pharmaceutically acceptable salts thereof as synergistic components, the bright yellow appearance of the Cur-HP- β -CD inclusion compound has an excellent optical covering effect on chlorphenamine maleate and methyl ephedrine hydrochloride, and can protect the stable quality and high efficiency of ultralow-concentration chlorphenamine maleate and methyl ephedrine hydrochloride, thereby ensuring the stable quality and high efficiency of the compound paracetamol and chlorphenamine maleate granules, and avoiding the side effect, adverse reaction, high-concentration ephedrine hydrochloride excess problem of higher-concentration main medicines and the problem of lower-concentration main medicines that the quality stability of the drug effect is reduced.
Further, the hydroxypropyl- β -cyclodextrin mixture with varying degrees of substitution comprises:
hydroxypropyl- β -cyclodextrin with DS ═ 5.4, and
hydroxypropyl- β -cyclodextrin with DS ═ 8.2,
wherein, the content of hydroxypropyl- β -cyclodextrin with DS 5.4 is not less than 83.0 mol%.
Further, the hydroxypropyl- β -cyclodextrin having a DS of 5.4 in the hydroxypropyl- β -cyclodextrin mixture having different degrees of substitution accounts for not less than 90.0 mol%.
Still further, the hydroxypropyl- β -cyclodextrin having a DS of 5.4 in the hydroxypropyl- β -cyclodextrin mixture having different degrees of substitution was 93.0 mol%.
HP- β -CD (hydroxypropyl- β -cyclodextrin) is a hydroxypropylated derivative of β -cyclodextrin (formula (1)) which has a greatly improved water solubility compared to its parent, and generally recognized as a higher substitution degree of hydroxypropyl- β -cyclodextrin, the less its inclusion-acceptable substances such as curcumin monophosphate and/or its salt of the present application, because a higher substitution degree (DS > 8.0) may result in a host molecule (such as curcumin monophosphate and/or its salt of the present application) having reduced steric hindrance into the cavity, whereas the inventors of the present application have surprisingly found that by using a mixture of a low substitution degree (DS ═ 5.4) HP- β -CD and a high substitution degree (DS ═ 8.2) HP- β -CD as curcumin monophosphate and/or its salt in a specific molar ratio, the inclusion ratio of the inclusion complex formed is significantly increased and the application efficiency thereof is increased, while the use of a low substitution degree (DS ═ 5.4) HP- β -CD, respectively, or a high substitution degree of HP- β -868-HP-CD, respectively, has a lower guest substitution degree of CD β, and a higher guest substitution degree of CD-868-HP-75, and a higher inclusion ratio of the same guest molecule is also decreased.
Further, the curcumin monophosphate and/or the salt thereof includes: curcumin monophosphate as shown in a formula (2), and mono-salt or di-salt of curcumin monophosphate; further, the salt is sodium salt, potassium salt, lithium salt, ammonium salt, magnesium salt or zinc salt; still further, the salt is curcumin monophosphate monosodium salt or curcumin monophosphate monolithium salt.
Further, the curcumin-based inclusion compound as the synergistic component is prepared by the following steps:
1) dissolving HP- β -CD in acid solution with pH of 2.0 to prepare 4.0-5.0 wt% HP- β -CD acid solution;
2) adding a large amount of absolute ethyl alcohol into the curcumin monophosphate and/or the salt thereof to dissolve the curcumin monophosphate;
3) dropwise adding the ethanol solution of curcumin monophosphate and/or curcumin monophosphate salt into HP- β -CD acid liquid in a gradually decreasing manner at constant temperature and constant rotating speed, introducing nitrogen after dropwise adding, sealing, and continuously stirring for inclusion in dark;
4) after balancing, the suspension is centrifuged at a high speed of not less than 20000r/min, and the supernatant is collected and lyophilized to obtain the product.
In the application, firstly, HP- β -CD is dissolved in acid liquor with the pH value of 2.0, HP- β -CD can be dissolved to the maximum, raw materials are saved, reaction efficiency is improved, then ethanol solution of curcumin monophosphate and/or salts thereof is dropwise added into HP- β -CD acid liquor in a gradually decreasing mode for inclusion, the inclusion rate of curcumin monophosphate and/or salts thereof and HP- β -CD can be improved to a large extent, the stability of the formed curcumin type inclusion compound in solutions with strong light irradiation, high temperature, high humidity and different pH values is obviously higher than that of the corresponding curcumin type inclusion compound and/or salts thereof on the premise that the color of the curcumin monophosphate and/or salts thereof is not obviously changed, the solubility and the dissolution rate are also obviously improved, and the curcumin type inclusion compound has positive effects on the aspects of ensuring stable and high efficiency of the quality of the compound paracetamol particle sensitive composition, avoiding side effects with higher concentration, adverse effects, reduction of the quality stability of the main drug with lower concentration.
Further, the acid solution with pH 2.0 in step 1) may be selected from citric acid solution, tartaric acid solution, hydrochloric acid solution, phosphoric acid solution, methanesulfonic acid solution; preferably from phosphoric acid solutions.
Further, the curcumin monophosphate in step 2) can be selected from curcumin monophosphate mono-salt or di-salt, preferably from sodium salt, potassium salt, lithium salt, ammonium salt, magnesium salt or zinc salt, and more preferably from curcumin monophosphate mono-sodium salt or curcumin monophosphate mono-lithium salt.
Further, the constant temperature and constant rotation speed in the step 3) is specifically as follows: keeping the temperature at 40-50 ℃, preferably 42 ℃; the constant rotating speed is 60-180 r/min, preferably 120-150 r/min.
Further, the step 3) of dropping in a gradually decreasing manner means that the dropping amount V in the i min isiAnd the dropping amount V in 1min1The relationship (2) corresponds to the formula (3): vi=V1×[(102-2i)]Percent (3) wherein i is 1 to imaxI is an integer of 10 to imaxThe curcumin monophosphate and/or the salt thereof are dropwise added into the HP- β -CD acid liquor in a gradually decreasing mode, namely the dropwise adding is required to be completed within 10-20 min, in the process of preparing the synergistic component curcumin analog inclusion compound, as the curcumin monophosphate and/or the salt thereof in the ethanol suddenly enters a large amount of acid liquor, the precipitation of the curcumin monophosphate and/or the salt thereof is inevitable, the gradually decreasing dropwise adding of the ethanol solution of the curcumin monophosphate and/or the salt thereof in the application can effectively avoid the precipitation, and particularly, the precipitation is not gradually selectedThe same effect can be obtained by the dropping method with decreasing, and the following dropping method with decreasing the dropping amount within 1 min/the dropping amount within the first 1min of 90% or 95% inevitably causes precipitation, and the accompanying disadvantages also include the decrease of the inclusion rate.
Further, the inclusion temperature in the step 3) is 40-50 ℃, preferably 42 ℃; the inclusion time is 8-24 h, preferably 12-16 h.
Further, during the freeze-drying in the step 4), the pressure is controlled to be less than 10Pa, the mixture is pre-frozen for 4-6 h at the temperature of-50 to-60 ℃, and then the mixture is freeze-dried for 24h at the temperature of-60 to-80 ℃.
Further, in the method for preparing the curcumin-based inclusion compound with the synergistic component, the molar ratio of the curcumin monophosphate and/or the salt thereof to the HP- β -CD is 1: 2-5, preferably 1: 3.0-3.5, and the relationship between the substitution Degree (DS) and the average molecular weight (M) of the HP- β -CD is shown as formulas (4) and (5).
Ds=[(∑Hi×Mi/∑Hi)-1157]/58 (4)
M=DS×58+1135 (5)
In formulae (4) and (5), HiAnd MiThe peak height and mass of the molecular ion peak, 1135 is the molecular weight of β -CD, 1157 is [ β -CD + Na ], respectively]+58 is the molecular weight of 1 hydroxypropyl group.
Furthermore, in the compound paracetamol and chlorphenamine maleate granules, the mass ratio of the acetaminophen, the chlorphenamine maleate, the methamphetamine hydrochloride, the curcumin compound and the powdered sugar is 100-500: 1: 1-5: 1-10: 3000-10000.
Further, the sugar powder is sucrose powder, which is pulverized and then passed through a sieve of at least 80 meshes.
Further, the compound paracetamol and chlorphenamine maleate granules also comprise other auxiliary material components, and the compound paracetamol and chlorphenamine maleate granules specifically comprise:
the weight ratio of the artificial bezoar to the chlorpheniramine maleate is 1-10: 1.
The weight ratio of the adhesive to the chlorpheniramine maleate is 0.1-5.0: 1, and the adhesive can be selected from one or more of gelatin, sodium carboxymethyl cellulose, povidone K30 and dextrin; and
the weight ratio of the essence to the chlorphenamine maleate is 0.2-1.0: 1, and the essence can be one or more of stevioside, aspartame, strawberry essence, orange essence and hawthorn essence.
[2] The process for producing the compound paracetamol and chlorphenamine maleate granules according to item [1], which comprises:
A) preparing the curcumin complex;
B) adding a proper amount of water into the chlorphenamine maleate and curcumin inclusion compound to prepare a solution A;
C) mixing acetaminophen, methyl ephedrine hydrochloride and sugar powder, and adding appropriate amount of water to obtain mucus B;
D) adding the solution A into the solution B, mixing uniformly, adding or not adding other auxiliary material components, preparing into soft material, granulating, drying and finishing.
The step D) of uniformly mixing can adopt the prior art of stirring for at least 30min and the like to realize uniform mixing.
And D), granulating by using a screen of 20-40 meshes, preferably 40 meshes.
And the drying in the step D) is carried out at the temperature of 45-60 ℃ until the weight is constant.
And D) finishing the granules by using a screen with 10-40 meshes.
The preparation method is simple and feasible, can be completed by using the existing granulation process, and the prepared compound paracetamol and chlorphenamine maleate granules can be used in medicines for treating common cold or influenza, have stable and reliable drug effect, and can keep stable quality even if chlorphenamine maleate and methyl ephedrine hydrochloride are in ultralow concentration, thereby ensuring stable and efficient quality of the compound paracetamol and chlorphenamine maleate granules, and avoiding the problems of side effect and adverse reaction of main medicines with higher concentration and reduction of drug effect and quality stability of main medicines with lower concentration.
[3] Use of the compound paracetamol and chlorphenamine maleate granules according to any one of the items [2] or [3] in the preparation of a medicament for preventing and/or treating cold, wherein the cold is common cold or influenza.
The invention has the beneficial effects that:
1) the inclusion rate of the formed inclusion compound is remarkably improved by taking a mixture containing a low-substitution-degree (DS ═ 5.4) HP- β -CD and a high-substitution-degree (DS ═ 8.2) HP- β -CD in a specific molar ratio as a guest inclusion curcumin monophosphate and/or a salt thereof;
2) the ethanol solution of the curcumin monophosphate and/or the salt thereof is dropwise added into HP- β -CD acid solution for inclusion in a gradually decreasing mode, so that the inclusion rate of the curcumin monophosphate and/or the salt thereof and HP- β -CD can be improved to a greater extent, and on the premise that the color and luster of the curcumin monophosphate and/or the salt thereof are not significantly changed, the stability of the formed curcumin type inclusion compound in solutions with strong light irradiation, high temperature, high humidity and different pH values is obviously higher than that of the corresponding curcumin monophosphate and/or the salt thereof, the solubility and the dissolution rate are also significantly improved, and the curcumin type inclusion compound ensures that the quality of the compound paracetamol particle composition is stable and efficient;
3) the Cur-HP- β -CD inclusion compound formed by inclusion of curcumin monophosphate and/or pharmaceutically acceptable salts thereof in hydroxypropyl- β -cyclodextrin mixtures with different substitution degrees is used as a synergistic component, the bright yellow appearance of the Cur-HP- β -CD inclusion compound has an excellent optical covering effect on chlorpheniramine maleate and methylephedrine hydrochloride, and the ultra-low concentration chlorpheniramine maleate and methylephedrine hydrochloride can be protected to be stable in quality, so that the compound paracetamol granule composition is stable in quality and high in efficiency, and the problems of side effects, adverse reactions, the excessive problem of high-concentration methylephedrine hydrochloride and the problem of reduction of the quality of the drug effect of the low-concentration main drug are avoided.
The invention adopts the technical scheme to provide the model essay, makes up the defects of the prior art, and has reasonable design and convenient operation.
Drawings
In order to make the aforementioned and other objects, features, and advantages of the invention, as well as others which will become apparent, reference is made to the following description taken in conjunction with the accompanying drawings in which:
FIG. 1 is a schematic structural diagram of hydroxypropyl- β -cyclodextrin of the present invention;
FIG. 2 is a schematic representation of the preparation of inclusion complexes using HP- β -CD inclusion guest molecules according to the present invention;
FIG. 3 is a schematic structural diagram of curcumin monophosphate of the present invention;
fig. 4 is a statistical schematic diagram of the inclusion rate of the curcumin-based inclusion compound in the embodiment of the present invention.
Detailed Description
Unless defined otherwise, technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The present invention uses the methods and materials described herein; other suitable methods and materials known in the art may be used. The materials, methods, and examples described herein are illustrative only and are not intended to be limiting. All publications, patent applications, patents, provisional applications, database entries, and other references mentioned herein, and the like, are incorporated by reference herein in their entirety. In case of conflict, the present specification, including definitions, will control.
All percentages, parts, ratios, etc., are by weight, "mol%" means mole percent, unless otherwise indicated.
Herein, the term "made from … …" is equivalent to "comprising". As used herein, the terms "comprises," "comprising," "includes," "including," "has," "having," "contains," or any other variation thereof, are intended to cover a non-exclusive inclusion. For example, a composition, process, method, article, or apparatus that comprises a list of elements is not necessarily limited to only those elements but may include other elements not expressly listed or inherent to such composition, process, method, article, or apparatus.
The conjunction "consisting of … … does not include any elements, steps or components not expressly listed. If present in a claim, the conjunction will limit the claim to the described materials and not to materials not described, but will still include impurities normally associated with those described materials. When the conjunction "consisting of … …" appears in the characterizing portion of the claim, rather than in the immediately preceding portion, it is limited to the elements set forth in the characterizing portion; other elements are not excluded from the claim as a whole.
The conjunction "consisting essentially of … …" is used to define a composition, method, or apparatus that includes additional materials, steps, features, components, or elements in addition to those materials, steps, features, components, or elements that are literally set forth, provided that such additional materials, steps, features, components, or elements do not materially affect the basic and novel characteristics of the claimed invention. The term "consisting essentially of … …" is in the intermediate zone between "comprising" and "consisting of … …".
The term "comprising" is intended to include embodiments encompassed by the terms "consisting essentially of … …" and "consisting of … …". Similarly, the term "consisting essentially of … …" is intended to include embodiments encompassed by the term "consisting of … …".
When an amount, concentration, or other value or parameter is given as either a range, preferred range or a list of upper preferable values and lower preferable values, this is to be understood as specifically disclosing all ranges formed from any pair of any upper range limit or preferred value and any lower range limit or preferred value, regardless of whether ranges are separately disclosed. For example, when a range of "1 to 5" is described, the described range should be understood to include ranges of "1 to 4", "1 to 3", "1 to 2 and 4 to 5", "1 to 3 and 5", and the like. Where numerical ranges are described herein, unless otherwise stated, the ranges are intended to include the endpoints of the ranges, and all integers and fractions within the ranges.
When the term "about" is used to describe a numerical value or an end point value of a range, the disclosure should be understood to include the specific value or end point referred to.
Furthermore, "or" means "or" unless expressly indicated to the contrary, rather than "or" exclusively. For example, condition a "or" B "applies to any of the following conditions: a is true (or present) and B is false (or not present), a is false (or not present) and B is true (or present), and both a and B are true (or present).
In addition, the indefinite articles "a" and "an" preceding an element or component of the invention are intended to mean no limitation on the number of occurrences (i.e., occurrences) of the element or component. Thus, "a" or "an" should be understood to include one or at least one and the singular forms of an element or component also include the plural unless the singular is explicitly stated.
Embodiments of the present invention, including embodiments of the invention described in the summary section as well as any other embodiments described herein below, can be combined arbitrarily and the description of the variables in the embodiments applies not only to the complexed paracetamol particles of the present invention, but also to pharmaceutical products made from the complexed paracetamol particles.
The materials, methods, and examples described herein are illustrative only and not intended to be limiting unless otherwise specified. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described herein.
The present invention is described in detail below.
Example 1: a compound paracetamol and chlorphenamine maleate granule formula comprises:
this embodiment provides a compound paracetamol and chlorpheniramine maleate particle comprising:
the main effective components are acetaminophen, chlorphenamine maleate and methyl ephedrine hydrochloride;
synergistic component, which is curcumin compound; and
powdered sugar, which is crushed and then screened by a 100-mesh screen;
the curcumin inclusion compound is prepared by including a mixture which is composed of HP- β -CD with 93.0 mol% DS-5.4 and HP- β -CD with 7.0 mol% DS-8.2 and taking curcumin monophosphate mono-lithium salt as a guest.
The synergistic component curcumin complex is prepared by the following steps:
1) 40.40g of HP- β -CD with DS being 5.4 and 3.38g of HP- β -CD with DS being 8.2 are dissolved in phosphoric acid with pH being 2.0 to prepare 4.2 wt% of HP- β -CD acid solution;
2)4.47g of curcumin monophosphate monolithium salt is dissolved by adding a large amount of absolute ethyl alcohol;
3) dropwise adding the ethanol solution of mono lithium salt of curcumin monophosphate into HP- β -CD acid liquor in a gradually decreasing manner within 15min at a constant temperature of 42 ℃ and a stable rotation speed of 120r/min, introducing nitrogen after dropwise adding, sealing, and continuously stirring in the dark for inclusion for 12 h;
4) after balancing, the suspension is centrifuged at 24000r/min at high speed, and the supernatant is collected and lyophilized to obtain the finished product.
The step 3) of dropping in a gradually decreasing manner means that the dropping amount V in the ith min isiAnd the dropping amount V in 1min1The relationship (2) corresponds to the formula (3): vi=V1×[(102-2i)]Percent (3), wherein i is an integer between 1 and 15; that is, the dropping amount V at 2min2Is the 1 st min dropping amount V198% of (1), the dropping amount V at 3min3Is the 1 st min dropping amount V196% of (1), the 4 th min dropping amount V4Is the 1 st min dropping amount V194%, … … of (1), until the 15 th min of dropping amount V15Is the 1 st min dropping amount V172% of the total amount, V can be calculated1And V can be calculated2、V3、V4、……、V15And the dropping can be completed in each dropping amount.
And 4) during freeze-drying, controlling the pressure to be 8Pa, pre-freezing for 4.5h at-55 ℃, and then freeze-drying for 24h at-80 ℃.
The embodiment also provides a preparation method of the compound paracetamol and chlorphenamine maleate granules, which specifically comprises the following steps:
A) preparing the curcumin complex;
B) adding appropriate amount of water into 1.0g chlorphenamine maleate and 5.0g curcumin clathrate to obtain solution A;
C)140g of acetaminophen, 1.2g of methylephedrine hydrochloride and 5500g of sugar powder are mixed uniformly, and a proper amount of water is added to prepare mucus B;
D) adding solution A into solution B, mixing, adding artificial bezoar 3.0g, carboxymethyl fiber 0.4g and steviosin 0.8g, mixing, making into soft material, granulating, drying and grading.
Specifically, the above-mentioned preparation method further includes the following limitations (a) to (g):
(a) step a) preparation of the curcumin complex was prepared according to the specific preparation steps of this example;
(b) the appropriate amount of water for step B) was 200 g;
(c) the appropriate amount of water for step C) was 3500 g;
(d) the step C) and the step D) are uniformly mixed by stirring at 120r/min for 30 min;
(e) the granulation in the step D) is granulation by a 40-mesh screen;
(f) the drying of step D) is drying at a temperature of 52 ℃ to constant weight;
(g) the whole grain in the step D) is finished by a 30-mesh screen.
Example 2: the other compound paracetamol and chlorphenamine maleate granules comprise the following components in parts by weight:
the formulation of the compound paracetamol and chlorpheniramine maleate granules and the preparation method thereof in the present example are substantially the same as example 1, except that in the present example, when the synergistic curcumin compound is prepared, the addition amount of HP- β -CD with DS of 5.4 is 40.40g, the addition amount of HP- β -CD with DS of 4.2 is 2.90g, that is, the molar ratio of HP- β -CD with DS of 5.4 to HP- β -CD with DS of 4.2 is 93.0: 7.0.
Example 3: the other compound paracetamol and chlorphenamine maleate granules comprise the following components in parts by weight:
the formulation of the compound paracetamol and chlorpheniramine maleate granules and the preparation method thereof in this example are substantially the same as example 1, except that in this example, when the synergistic curcumin compound is prepared, HP- β -CD with DS of 7.4 is used in an amount of 43.64g, HP- β -CD with DS of 8.2 is used in an amount of 3.38g, that is, the molar ratio of HP- β -CD with DS of 7.4 to HP- β -CD with DS of 4.2 is 93.0: 7.0.
Example 4: another compound paracetamol and chlorphenamine maleate granuleThe method comprises the following steps:
the formulation of the compound paracetamol and chlorpheniramine maleate granules and the preparation method thereof in the present example are substantially the same as example 1, except that in the present example, when the synergistic curcumin compound is prepared, the addition amount of HP- β -CD with DS of 5.4 is 21.72g, the addition amount of HP- β -CD with DS of 8.2 is 24.16g, namely, the molar ratio of HP- β -CD with DS of 5.4 to HP- β -CD with DS of 8.2 is 1: 1.
Example 5: the other compound paracetamol and chlorphenamine maleate granules comprise the following components in parts by weight:
the formulation of the compound paracetamol and chlorpheniramine maleate granules and the preparation method thereof in the present example are substantially the same as example 1, except that in the present example, when the synergistic curcumin compound is prepared, the addition amount of HP- β -CD with DS of 5.4 is 3.04g, the addition amount of HP- β -CD with DS of 8.2 is 44.94g, that is, the molar ratio of HP- β -CD with DS of 5.4 to HP- β -CD with DS of 8.2 is 7.0: 93.0.
Example 6: the other compound paracetamol and chlorphenamine maleate granules comprise the following components in parts by weight:
the formulation of the compound paracetamol and chlorpheniramine maleate granules and the preparation method thereof in the embodiment are basically the same as that in the embodiment 1, except that in the embodiment, when the synergistic component curcumin compound is prepared, the addition amount of HP- β -CD with DS being 5.4 is 43.45g, and the addition amount of HP- β -CD with DS being 8.2 is 0g, namely HP- β -CD in the preparation of the curcumin compound consists of single HP- β -CD with DS being 5.4, the other component proportions and the preparation process are the same as those in the embodiment 1, and the compound paracetamol and chlorpheniramine maleate granules are finally prepared.
Example 7: the other compound paracetamol and chlorphenamine maleate granules comprise the following components in parts by weight:
the formulation of the compound paracetamol and chlorpheniramine maleate granules and the preparation method thereof in the embodiment are basically the same as that in the embodiment 1, except that in the embodiment, when the synergistic component curcumin compound is prepared, the addition amount of HP- β -CD with DS being 5.4 is 0g, and the addition amount of HP- β -CD with DS being 8.2 is 48.32g, namely HP- β -CD in the preparation of the curcumin compound consists of single HP- β -CD with DS being 8.2, the other component proportions and the preparation process are the same as those in the embodiment 1, and the compound paracetamol and chlorpheniramine maleate granules are finally prepared.
Example 8: the formula of the compound paracetamol and chlorphenamine maleate granules comprises the following components in parts by weight:
the formula and the preparation method of the compound paracetamol and chlorphenamine maleate granules in the embodiment are basically the same as those in the embodiment 1, except that in the embodiment, when the synergistic component curcumin compound is prepared, the step 3) of dropwise adding in a gradually decreasing mode specifically refers to the following steps: the dropping amount in the latter 1min was 95% of the dropping amount in the former 1min, that is, the dropping amount V in the 2 nd min2Is the 1 st min dropping amount V195% of (1), the dropping amount V at 3min3Is the 2 nd min dropping amount V295% of (1), 4min of the amount of dropwise addition V4Is the 3 rd min dropping amount V395% of (C), … …, until 15min15Is the 14 th min dropping amount V1495% of the total amount, V can be calculated1And V can be calculated2、V3、V4、……、V15The dropping can be completed according to each dropping amount, and micro crystals are separated out in the process. The proportion of the other components and the preparation process are the same as those of the example 1, and the compound paracetamol and chlorphenamine maleate granules are finally prepared.
Example 9: the formula of the compound paracetamol and chlorphenamine maleate granules comprises the following components in parts by weight:
the formula and the preparation method of the compound paracetamol and chlorphenamine maleate granules in the embodiment are basically the same as those in the embodiment 1, except that in the embodiment, when the synergistic component curcumin compound is prepared, the dripping mode in the step 3) is carried out in a mode of weighing every dripping, and specifically, the formula and the preparation method are as follows: amount of dropwise added V within each minute1、V2、V3、V4、……、V15Equal to 1/15, which is the total amount of the ethanol solution of the mono-lithium salt of curcumin monophosphate, and can be added according to the adding amount, and a small amount of crystals are separated out in the process. The proportion of the other components and the preparation process are the same as those of the example 1, and the compound paracetamol and chlorphenamine maleate granules are finally prepared.
Example 10: a compoundThe formula of the paracetamol and chlorphenamine maleate granules comprises the following components:
the formula and the preparation method of the compound paracetamol and chlorphenamine maleate granules in the embodiment are basically the same as those in the embodiment 1, except that in the embodiment, when the synergistic component curcumin compound is prepared, the step 3) is to perform dropwise adding in a gradually increasing mode, specifically: the dropping amount in the latter 1min was 105% of the dropping amount in the first 1min, that is, the dropping amount V in the 2 nd min2Is the 1 st min dropping amount V1105% of (1), the dropping amount V at 3min3Is the 2 nd min dropping amount V2105% of (1), the 4 th min dropping amount V4Is the 3 rd min dropping amount V3105%, … …, until 15min15Is the 14 th min dropping amount V14105% of the total amount, V can be calculated1And V can be calculated2、V3、V4、……、V15The dropping can be completed according to each dropping amount, and a large amount of crystals are separated out in the process. The proportion of the other components and the preparation process are the same as those of the example 1, and the compound paracetamol and chlorphenamine maleate granules are finally prepared.
Example 11: the formula of the compound paracetamol and chlorphenamine maleate granules comprises the following components in parts by weight:
the formula and the preparation method of the compound paracetamol and chlorphenamine maleate granules in the embodiment are basically the same as those in the embodiment 1, except that in the embodiment, the addition amount of the curcumin compound is 0.1g when the compound paracetamol and chlorphenamine maleate granules are compounded and prepared. The proportion of the other components and the preparation process are the same as those of the example 1, and the compound paracetamol and chlorphenamine maleate granules are finally prepared.
Example 12: the formula of the compound paracetamol and chlorphenamine maleate granules comprises the following components in parts by weight:
the formula and the preparation method of the compound paracetamol and chlorphenamine maleate granules in the embodiment are basically the same as those in the embodiment 1, except that in the embodiment, the addition amount of the curcumin compound is 0g when the compound paracetamol and chlorphenamine maleate granules are compounded and prepared. The proportion of the other components and the preparation process are the same as those of the example 1, and the compound paracetamol and chlorphenamine maleate granules are finally prepared.
Example 13: the formula of the compound paracetamol and chlorphenamine maleate granules comprises the following components in parts by weight:
the formulation and preparation method of the compound paracetamol and chlorphenamine maleate granules of this example are substantially the same as example 1, except that in this example, the amount of the methylephedrine hydrochloride added is 0g when the compound paracetamol and chlorphenamine maleate granules are compounded and prepared. The proportion of the other components and the preparation process are the same as those of the example 1, and the compound paracetamol and chlorphenamine maleate granules are finally prepared.
Example 14: the formula of the compound paracetamol and chlorphenamine maleate granules comprises the following components in parts by weight:
the formulation and preparation method of the compound paracetamol and chlorphenamine maleate granules of this example are substantially the same as example 1, except that in this example, the amount of the methylephedrine hydrochloride added is 0.1g when the compound paracetamol and chlorphenamine maleate granules are compounded and prepared. The proportion of the other components and the preparation process are the same as those of the example 1, and the compound paracetamol and chlorphenamine maleate granules are finally prepared.
Experimental example 1: detection of inclusion rate of curcumin compound:
accurately weighing a proper amount of curcumin complex freeze-dried products, adding a small amount of absolute ethyl alcohol, performing ultrasonic treatment for 20min, transferring the obtained product to a 100mL brown volumetric flask, adding the absolute ethyl alcohol to dilute the product to a scale, measuring the absorbance of the complex at a wavelength of 423nm by taking the absolute ethyl alcohol as a blank, obtaining the curcumin content in the complex according to a regression equation, and calculating the inclusion rate according to a formula (6):
inclusion rate ═ CE/CT)×100%(6)
In the formula (6), CEIs the weight of the included curcumin substance measured by ultraviolet spectrophotometry at 423nm, CTIs the total weight of the curcumin initially added.
The inclusion rate of the curcumin-based inclusion compounds in examples 1-10 was tested according to the method of the present experimental example, and the statistical data is shown in fig. 2, it can be seen from the graph of fig. 2 that the inclusion rate of the curcumin-based inclusion compound in the preferred example 1 of the present application is the highest and exceeds 95%, while in the other examples, no matter the low-substitution-degree HP- β -CD mixture, the high-substitution-degree HP- β -CD mixture, the single high-or low-substitution-degree HP- β -CD mixture, or the substitution-degree-changed HP- β -CD mixture is used as an inclusion guest, or the ethanol solution of curcumin monophosphate and/or its salt is dripped into the HP- β -CD acid solution in a manner of measurement, gradual increase or gradual decrease different from the decrease manner described in the present application, the inclusion rate of the curcumin-based inclusion compound obtained is significantly reduced, and the bioavailability thereof can be deduced to be reduced.
Example 2: detecting the physical and chemical properties of the compound paracetamol and chlorphenamine maleate granules:
A. and (3) detecting characters:
the granules in examples 1 to 14 were sampled according to the sampling method specified in the national pharmacopoeia, 5 samples were taken for each example, and the color and luster thereof were examined and the statistical results are shown in table 1. The above examination results show that the properties of the compound paracetamol and chlorphenamine maleate granules obtained by the invention all meet the requirements of national standards.
TABLE 1 Compound Paracetamol and chlorphenamine maleate granules
B. And (3) detecting the dissolubility:
according to the sampling method specified by the national pharmacopoeia, the compound paracetamol and chlorphenamine maleate particles in the embodiments 1 to 14 are respectively sampled, 5 samples are taken in each embodiment, 10g of each sample is sampled to carry out the dissolubility inspection, the detection method is inspected according to the dissolubility inspection method under the item of the Chinese pharmacopoeia (2015 edition four parts) granules, the inspection result shows that all the compound paracetamol and chlorphenamine maleate particles in the embodiments 1 to 14 are qualified, and the formula and the process parameters thereof are reasonable.
C. And (3) detecting the content of chlorpheniramine maleate:
according to the sampling method specified in the national pharmacopoeia, all the compound paracetamol and chlorphenamine maleate granules in the embodiments 1 to 14 of the application are sampled, 5 samples are taken in each embodiment, the content of chlorphenamine maleate is detected according to the high performance liquid chromatography in the Chinese pharmacopoeia (2015 four parts), and the detection results are shown in table 2.
TABLE 2 Chlorophenylamine maleate content
As can be seen from the table 2, the curcumin compound with high inclusion rate in the application has a positive effect on maintaining the drug effect of ultra-low-content chlorphenamine maleate, so that the stable quality and high efficiency of the compound paracetamol and chlorphenamine maleate particle composition are ensured.
D. Detecting the content of the methylephedrine hydrochloride:
according to the sampling method specified in the national pharmacopoeia, all the compound paracetamol and chlorphenamine maleate granules in the embodiments 1 to 14 of the application are sampled, 5 samples are taken in each embodiment, and the detection results are shown in table 3 according to the detection of the methylephedrine hydrochloride according to the Chinese pharmacopoeia (2015 th part).
TABLE 3 content of Methylephedrine hydrochloride
As can be seen from table 3, the curcumin-based inclusion compound with high inclusion rate in the present application has a positive effect on maintaining the efficacy of ultra-low content of methamphetamine hydrochloride, thereby ensuring stable quality and high efficiency of the compound paracetamol and chlorphenamine maleate particle composition, and in addition, as can be seen from the data in example 14, the ultra-low dosage content of methamphetamine hydrochloride is easy to lose efficacy.
Conventional techniques in the above embodiments are known to those skilled in the art, and therefore, will not be described in detail herein.
While the above detailed description has shown, described, and pointed out novel features as applied to various embodiments, it will be understood that various omissions, substitutions, and changes in the form and details of the device or method illustrated may be made without departing from the spirit of the disclosure. In addition, the various features and methods described above may be used independently of one another, or may be combined in various ways. All possible combinations and sub-combinations are intended to fall within the scope of the present disclosure. Many of the embodiments described above include similar components, and thus, these similar components are interchangeable in different embodiments. While the invention has been disclosed in the context of certain embodiments and examples, it will be understood by those skilled in the art that the invention extends beyond the specifically disclosed embodiments to other alternative embodiments and/or uses and obvious modifications and equivalents thereof. Accordingly, the invention is not intended to be limited by the specific disclosure of preferred embodiments herein.
Claims (10)
1. A compound paracetamol and chlorphenamine maleate particle comprising:
the main effective components are acetaminophen, chlorphenamine maleate and methyl ephedrine hydrochloride;
synergistic component, which is curcumin compound; and
powdered sugar;
the curcumin complex is prepared by taking hydroxypropyl- β -cyclodextrin mixture with different degrees of substitution as a main body and taking curcumin monophosphate and/or salts thereof as a guest.
2. The paracetamol and chlorphenamine maleate granules according to claim 1 wherein the hydroxypropyl- β -cyclodextrin mixture having different degrees of substitution comprises:
hydroxypropyl- β -cyclodextrin with DS ═ 5.4, and
hydroxypropyl- β -cyclodextrin with DS ═ 8.2,
wherein, the content of hydroxypropyl- β -cyclodextrin with DS 5.4 is not less than 83.0 mol%.
3. The paracetamol and chlorphenamine maleate granules according to claim 1 or 2 wherein the hydroxypropyl- β -cyclodextrin mixture with DS 5.4 is present in an amount of not less than 90.0 mol% based on the total amount of hydroxypropyl- β -cyclodextrin with different degrees of substitution.
4. A compound paracetamol particle according to claim 1 or 2, wherein: the curcumin monophosphate and/or the salt thereof comprises: curcumin monophosphate, and mono-or di-salts of curcumin monophosphate.
5. A compound paracetamol and chlorphenamine maleate particle according to any one of claims 1 to 4 wherein: the synergistic component curcumin complex is prepared by the following steps:
1) dissolving HP- β -CD in acid solution with pH of 2.0 to prepare 4.0-5.0 wt% HP- β -CD acid solution;
2) adding a large amount of absolute ethyl alcohol into the curcumin monophosphate and/or the salt thereof to dissolve the curcumin monophosphate;
3) dropwise adding the ethanol solution of curcumin monophosphate and/or curcumin monophosphate salt into HP- β -CD acid liquid in a gradually decreasing manner at constant temperature and constant rotating speed, introducing nitrogen after dropwise adding, sealing, and continuously stirring for inclusion in dark;
4) after balancing, the suspension is centrifuged at a high speed of not less than 20000r/min, and the supernatant is collected and lyophilized to obtain the product.
6. Compound paracetamol particles according to claim 5, wherein: the step 3) of dropping in a gradually decreasing manner means that the dropping amount V in the ith min isiAnd the dropping amount V in 1min1The relationship (2) corresponds to the formula (3):
Vi=V1×[(102-2i)]% (3),
in the formula (3), i is 1 to imaxI is an integer of 10 to imax≤20。
7. Compound paracetamol particles according to claim 5, wherein: and 4) during freeze-drying, controlling the pressure to be less than 10Pa, pre-freezing for 4-6 h at-50 to-60 ℃, and then freeze-drying for 24h at-60 to-80 ℃.
8. A compound paracetamol and chlorphenamine maleate particle according to any one of claims 1 to 7 wherein: the compound paracetamol and chlorphenamine maleate granules also comprise other auxiliary material components, and specifically comprise the following components:
the weight ratio of the artificial bezoar to the chlorpheniramine maleate is 1-10: 1.
The weight ratio of the adhesive to the chlorpheniramine maleate is 0.1-5.0: 1, and the adhesive can be selected from one or more of gelatin, sodium carboxymethyl cellulose, povidone K30 and dextrin; and
the weight ratio of the essence to the chlorphenamine maleate is 0.2-1.0: 1, and the essence can be one or more of stevioside, aspartame, strawberry essence, orange essence and hawthorn essence.
9. A process for preparing the compound paracetamol and chlorpheniramine maleate granules according to any one of claims 1 to 8, which comprises:
A) preparing the curcumin complex;
B) adding a proper amount of water into the chlorphenamine maleate and curcumin inclusion compound to prepare a solution A;
C) mixing acetaminophen, methyl ephedrine hydrochloride and sugar powder, and adding appropriate amount of water to obtain mucus B;
D) adding the solution A into the solution B, mixing uniformly, adding or not adding other auxiliary material components, preparing into soft material, granulating, drying and finishing.
10. Use of the compound paracetamol and chlorpheniramine maleate granules according to any one of claims 1 to 9 for the preparation of a medicament for the prevention and/or treatment of cold, wherein the cold is common cold or influenza.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201911300698.8A CN110934833B (en) | 2019-12-17 | 2019-12-17 | Compound paracetamol and chlorphenamine maleate granules |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201911300698.8A CN110934833B (en) | 2019-12-17 | 2019-12-17 | Compound paracetamol and chlorphenamine maleate granules |
Publications (2)
Publication Number | Publication Date |
---|---|
CN110934833A true CN110934833A (en) | 2020-03-31 |
CN110934833B CN110934833B (en) | 2022-08-19 |
Family
ID=69911229
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201911300698.8A Active CN110934833B (en) | 2019-12-17 | 2019-12-17 | Compound paracetamol and chlorphenamine maleate granules |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN110934833B (en) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN114796280A (en) * | 2022-06-15 | 2022-07-29 | 河北长天药业有限公司 | Compound paracetamol and chlorphenamine maleate granules and preparation process thereof |
CN115813864A (en) * | 2022-12-27 | 2023-03-21 | 石河子大学 | Curcumin instant granules and preparation method thereof |
Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN103800375A (en) * | 2014-03-10 | 2014-05-21 | 张春燕 | Medicine for alleviating or treating common colds and influenza symptoms and preparation method thereof |
CN104873983A (en) * | 2015-05-25 | 2015-09-02 | 福建省力菲克药业有限公司 | Curcumin cyclodextrin clathrate compound and preparation method thereof |
CN105367601A (en) * | 2015-12-03 | 2016-03-02 | 山东大学 | Curcumin derivative and preparation method therefor |
CN105377242A (en) * | 2013-06-06 | 2016-03-02 | 菲布罗根有限公司 | Pharmaceutical formulations of HIF hydroxylase inhibitor |
CN106474130A (en) * | 2016-08-31 | 2017-03-08 | 海南三风友制药有限公司 | A kind of compound recipe flu oral administration solution and preparation method thereof |
CN108685856A (en) * | 2018-07-26 | 2018-10-23 | 广东宏远集团药业有限公司 | Pediatric paracetamol granule and preparation method thereof |
CN108686004A (en) * | 2018-07-26 | 2018-10-23 | 广东宏远集团药业有限公司 | Particles for eliminating phlegm and stopping cough for children and preparation method thereof |
-
2019
- 2019-12-17 CN CN201911300698.8A patent/CN110934833B/en active Active
Patent Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN105377242A (en) * | 2013-06-06 | 2016-03-02 | 菲布罗根有限公司 | Pharmaceutical formulations of HIF hydroxylase inhibitor |
CN103800375A (en) * | 2014-03-10 | 2014-05-21 | 张春燕 | Medicine for alleviating or treating common colds and influenza symptoms and preparation method thereof |
CN104873983A (en) * | 2015-05-25 | 2015-09-02 | 福建省力菲克药业有限公司 | Curcumin cyclodextrin clathrate compound and preparation method thereof |
CN105367601A (en) * | 2015-12-03 | 2016-03-02 | 山东大学 | Curcumin derivative and preparation method therefor |
CN106474130A (en) * | 2016-08-31 | 2017-03-08 | 海南三风友制药有限公司 | A kind of compound recipe flu oral administration solution and preparation method thereof |
CN108685856A (en) * | 2018-07-26 | 2018-10-23 | 广东宏远集团药业有限公司 | Pediatric paracetamol granule and preparation method thereof |
CN108686004A (en) * | 2018-07-26 | 2018-10-23 | 广东宏远集团药业有限公司 | Particles for eliminating phlegm and stopping cough for children and preparation method thereof |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN114796280A (en) * | 2022-06-15 | 2022-07-29 | 河北长天药业有限公司 | Compound paracetamol and chlorphenamine maleate granules and preparation process thereof |
WO2023241662A1 (en) * | 2022-06-15 | 2023-12-21 | 河北长天药业有限公司 | Compound paracetamol and chlorphenamine maleate granule and process for preparing same |
CN114796280B (en) * | 2022-06-15 | 2024-06-25 | 河北长天药业有限公司 | Compound paracetamol and chlorphenamine maleate granules and preparation process thereof |
CN115813864A (en) * | 2022-12-27 | 2023-03-21 | 石河子大学 | Curcumin instant granules and preparation method thereof |
Also Published As
Publication number | Publication date |
---|---|
CN110934833B (en) | 2022-08-19 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN110934833B (en) | Compound paracetamol and chlorphenamine maleate granules | |
Pokharkar et al. | Ternary complexation of carvedilol, β-cyclodextrin and citric acid for mouth-dissolving tablet formulation | |
Ghumman et al. | Taro-corms mucilage-alginate microspheres for the sustained release of pregabalin: In vitro & in vivo evaluation | |
CN105640913B (en) | A kind of olmesartan medoxomil tablet and preparation method thereof | |
CN106943367B (en) | Afatinib maleate tablet and preparation method thereof | |
CN104688705B (en) | A kind of alpha lipoic acid sustained release tablets and preparation method thereof | |
CN106749174B (en) | A kind of sitafloxacin dihydrate crystal form, preparation method and combinations thereof tablet | |
CN103301081A (en) | Cefdinir dispersible tablet and preparation method thereof | |
OA10029A (en) | Inclusion complexes of n-ethoxycarbonyl-3-morpholino-sydnonimine or salts formed with cyclodextrin-derivatives,preparation thereof and pharmaceutical compositions containing the same | |
Solanki | Formulation and Evaluation of Floatable In Situ Gel of Ofloxacin | |
CN112986289A (en) | Consistency evaluation and detection method of amoxicillin capsules | |
CN108261397B (en) | High-content amoxicillin soluble powder and preparation method thereof | |
CN106580909B (en) | Solid pharmaceutical composition containing sarpogrelate hydrochloride | |
CN116270487B (en) | Pediatric paracetamol, chlorphenamine maleate granules and preparation method thereof | |
CN112022816B (en) | Piracetam tablet and preparation method thereof | |
CN117281780B (en) | Airotopaolamine dry suspension and preparation method thereof | |
Sasidhar et al. | Formulation and optimization of orodispersible tablets of olmesartan medoxomil | |
CN111991359B (en) | Analgin tablet and preparation method thereof | |
CN103142522B (en) | Etoposide tablet | |
US20220387477A1 (en) | Pharmaceutical compositions containing alginate oligosaccharaide diacid | |
DE19835823A1 (en) | Antibiotic composition useful for preparing stable aqueous suspensions | |
CN112656769B (en) | Cefdinir dispersible tablet | |
Alsaad | Solubility Enhancement of Ticagrelor by Different Complexation Methods | |
Kumar et al. | Isolation and evaluation of Basella alba linn. Leaf mucilage as release retardant in tablet formulation | |
CN107157926A (en) | A kind of preparation method of injection docetaxel |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant |