CN110934833B - Compound paracetamol and chlorphenamine maleate granules - Google Patents

Abstract

The present invention relates to the technical field of medicine, in particular to a compound paracetamol granule, which is characterized by comprising: main functional components, which are acetaminophen, chlorpheniramine maleate and methylephedrine hydrochloride; , is a curcumin class inclusion compound; And powdered sugar; Wherein, the curcumin class inclusion compound is the hydroxypropyl-β-cyclodextrin mixture with different degrees of substitution as the main body, with curcumin monophosphate and / or its salt as a guest, it is prepared by inclusion. The compound paracetamol granules can protect the quality stability of ultra-low concentration chlorpheniramine maleate and methylephedrine hydrochloride, thus ensuring the stable quality and high efficiency of the compound paracetamol granules composition, avoiding the high concentration of the main drug side effects, adverse reactions, overdose of high-concentration methylephedrine hydrochloride, and reduced stability of the efficacy and quality of the main drug at lower concentrations.

Description

A kind of compound paracetamol granule

technical field

The present invention relates to the technical field of medicine, in particular to a compound paracetamol granule.

Background technique

The main components of traditional compound paracetamol granules are acetaminophen and chlorpheniramine maleate. Among them, acetaminophen is an acetanilide antipyretic and analgesic drug, also known as paracetamol, which is a metabolite of phenacetin and belongs to aniline. The synthesis and release of prostaglandin PGE1 lead to peripheral vasodilation and sweating to achieve antipyretic effect. Its antipyretic effect is similar in intensity to aspirin, but has no obvious anti-inflammatory effect. The synthesis and release of amines, etc., increase the pain threshold and play an analgesic effect. It is a peripheral analgesic. Its effect is weaker than that of aspirin, and it is only effective for mild and moderate pain. Chlorpheniramine maleate is an H1 receptor antagonist. Its chemical structure belongs to hydrocarbon amines. It can mainly competitively block histamine H1 receptors on allergy target cells, so that histamine cannot bind to H1 receptors. thereby inhibiting the allergic reaction it causes. But chlorpheniramine does not affect the metabolism of histamine, nor does it prevent the release of histamine in the body. In addition, chlorpheniramine maleate also has central inhibitory and anticholinergic effects, so after taking the drug, there are side effects such as drowsiness, dry mouth, constipation, thickened sputum and dry nasal mucosa. In order to reduce the side effects caused by the above-mentioned chlorpheniramine maleate, the stimulant substance ephedrine is often added. However, this move easily touched the safety limit of prescription drugs for the control of ephedrine stimulants. Ephedrine drugs bring hidden dangers. At the same time, ephedrine drugs are α and β receptor stimulants. Too high content has more side effects on the heart and central nervous system. Therefore, patients with hypertension, coronary heart disease, hyperthyroidism, glaucoma, and benign prostatic hypertrophy And when used in children, overdose will occur with a little carelessness, so the above-mentioned people are included in the category of caution in clinical practice. However, the low content of chlorpheniramine maleate and ephedrine has the problem of stable and effective quality, so it is necessary to conduct in-depth research, in order to find a reasonable technical solution to make the main components still effective at ultra-low concentrations, and side effects And adverse reactions can be effectively controlled, so as to ensure that such cold medicines are managed in accordance with over-the-counter drugs, and more and better benefit patients.

The disclosure of the above background technology content is only used to assist the understanding of the inventive concept and technical solution of the present invention, and it does not necessarily belong to the prior art of this patent application. If there is no clear evidence that the above content has been disclosed on the filing date of this patent application The above background art should not be used to evaluate the novelty and inventive step of the present application.

SUMMARY OF THE INVENTION

The object of the present invention is to provide a compound paracetamol granule, which can protect the stable quality of ultra-low concentration chlorpheniramine maleate and methylephedrine hydrochloride, thereby ensuring compound paracetamol The quality of the granule composition is stable and high-efficiency, and the side effects and adverse reactions of the main drug at a higher concentration, the overdose problem of the high-concentration methylephedrine hydrochloride, and the problem of reducing the stability of the efficacy and quality of the main drug at a lower concentration are avoided.

The technical scheme that the present invention adopts for realizing the above-mentioned purpose is:

[1] A compound paracetamol granule, comprising:

The main functional components are acetaminophen, chlorpheniramine maleate and methylephedrine hydrochloride;

A synergistic ingredient, which is a curcumin-type inclusion complex; and

powdered sugar;

Wherein, the curcumin inclusion compounds are mainly composed of hydroxypropyl-β-cyclodextrin (HP-β-CD) mixtures with different degrees of substitution (DS), and curcumin monophosphate and/or The salt is the guest and is prepared by inclusion, as shown in Figure 2.

The application provides a compound paracetamol granule, which specifically uses chlorpheniramine maleate, acetaminophen and methylephedrine hydrochloride as main functional components, and uses hydroxypropyl-β-ring of different degrees of substitution as main functional components. Curcumin-hydroxypropyl-β-cyclodextrin (Cur-HP-β-CD) inclusion complex formed by inclusion of curcumin monophosphate and/or its pharmaceutically acceptable salt in the dextrin mixture as a The active ingredient, the bright yellow appearance of the Cur-HP-β-CD inclusion complex has an exceptionally excellent optical covering effect on chlorpheniramine maleate and methylephedrine hydrochloride, which can protect ultra-low concentration chlorobenzene maleate The quality of Namin and methylephedrine hydrochloride is stable, thereby ensuring the stable and efficient quality of the compound paracetamol granule composition, avoiding the side effects, adverse reactions of the main drug with a higher concentration, excessive problems of high concentration methylephedrine hydrochloride and The problem of reduced efficacy and quality stability of the main drug at lower concentrations.

Further, the hydroxypropyl-β-cyclodextrin mixture with different degrees of substitution comprises:

Hydroxypropyl-β-cyclodextrin with DS = 5.4, and

Hydroxypropyl-β-cyclodextrin with DS=8.2,

Among them, the proportion of hydroxypropyl-β-cyclodextrin with DS=5.4 is not less than 83.0mol%.

Further, the proportion of hydroxypropyl-β-cyclodextrin with DS=5.4 in the hydroxypropyl-β-cyclodextrin mixture with different degrees of substitution is not less than 90.0 mol%.

Still further, the proportion of hydroxypropyl-β-cyclodextrin with DS=5.4 in the hydroxypropyl-β-cyclodextrin mixture with different degrees of substitution is 93.0 mol%.

HP-β-CD (Hydroxypropyl-β-cyclodextrin) is a hydroxypropylated derivative of β-cyclodextrin (its structural formula is shown in formula (1)), and its water solubility is relatively high compared with its parent. Great improvement, and it is generally recognized that the higher the degree of substitution of hydroxypropyl-β-cyclodextrin, the less substances it can include such as curcumin monophosphate and/or its salts of the present application, Because, a high degree of substitution (DS>8.0) may produce steric hindrance to reduce the host molecule (such as the curcumin monophosphate and/or its salt of the present application) entering the cavity, but the inventors of the present application unexpectedly found , by including a mixture of low substitution degree (DS=5.4) HP-β-CD and high substitution degree (DS=8.2) HP-β-CD containing a specific molar ratio as a guest inclusion curcumin monophosphate and/or its salt, the inclusion rate of the formed inclusion complex can be significantly improved, and then its application efficiency can also be improved; and the use of low degree of substitution (DS=5.4) HP-β-CD or high degree of substitution (DS=8.2) HP-β-CD As a guest, the inclusion rate of β-CD is higher than that of the HP-β-CD mixture with low substitution degree, and the application effect of the inclusion compound is also reduced.

Further, the curcumin monophosphate and/or its salt include: curcumin monophosphate as shown in formula (2), and curcumin monophosphate monosalt or disalt; further, the described The salt is sodium salt, potassium salt, lithium salt, ammonium salt, magnesium salt or zinc salt; further, the salt is curcumin monophosphate monosodium salt or curcumin monophosphate monolithium salt.

Further, the synergistic component curcumin inclusion compound is prepared by the following steps:

1) HP-β-CD is dissolved in pH=2.0 acid solution to prepare 4.0-5.0wt% HP-β-CD acid solution;

2) adding a large amount of absolute ethanol in curcumin monophosphate and/or its salt to dissolve it;

3) Under the constant temperature and constant rotation speed, the ethanolic solution of curcumin monophosphate and/or its salt is added dropwise to the HP-β-CD acid solution in a gradually decreasing manner, and nitrogen is introduced and sealed after the dropwise addition is completed, and the solution is protected from light. Continue to stir and include;

4) After equilibration, the suspension is centrifuged at a high speed of not less than 20,000 r/min, and the supernatant is collected and lyophilized.

In this application, HP-β-CD is first dissolved in an acid solution with pH=2.0, which can maximize the dissolution of HP-β-CD, save raw materials and improve the reaction efficiency, and then gradually reduce curcumin monophosphate The ethanolic solution of the ester and/or its salt is added dropwise to the HP-β-CD acid solution for inclusion, which can greatly improve the inclusion rate of curcumin monophosphate and/or its salt and HP-β-CD, Moreover, under the premise that the color of curcumin monophosphate and/or its salt does not change significantly, the stability of the formed curcumin inclusion complexes in strong light irradiation, high temperature, high humidity and different pH solutions are significantly higher than Its corresponding curcumin monophosphate and/or its salt, the solubility and the dissolution rate can also be significantly improved, and the curcumin inclusion compound is to ensure that the quality of the compound paracetamol granule composition is stable and efficient, and avoids higher It has a positive effect on the side effects and adverse reactions of the main drug at a lower concentration, and the stability of the efficacy and quality of the main drug at a lower concentration is reduced.

Further, the acid solution with pH=2.0 in step 1) can be selected from citric acid solution, tartaric acid solution, hydrochloric acid solution, phosphoric acid solution, and methanesulfonic acid solution; preferably from phosphoric acid solution.

Further, the curcumin monophosphate salt in step 2) can be selected from curcumin monophosphate monosalt or disalt, preferably from sodium salt, potassium salt, lithium salt, ammonium salt, magnesium salt or zinc salt, more preferably From curcumin monophosphate monosodium salt or curcumin monophosphate monolithium salt.

Further, the constant temperature and constant rotation speed in step 3) are specifically: a constant temperature of 40-50° C., preferably 42° C.; a constant rotation speed of 60-180 r/min, preferably 120-150 r/min.

Further, in step 3), dripping in a gradually decreasing manner means that the relationship between the dripping amount V _i in the ith min and the dripping amount V ₁ in the 1 min complies with formula (3): V _i =V ₁ ×[(102-2i)]%(3), where i is an integer between 1 and i _max , 10≤i _max ≤20, that is to say, the ethanol solution of curcumin monophosphate and/or its salt is It should be added dropwise to the HP-β-CD acid solution in a gradually decreasing manner within 10-20 minutes. In the process of preparing said synergistic ingredient curcumin inclusion compound, because curcumin monophosphate in ethanol and/or its salt suddenly enters into a large amount of acid solution, it is inevitable that curcumin monophosphate and/or its salt will appear. The situation of salt precipitation, dripping the ethanolic solution of curcumin monophosphate and/or its salt can effectively avoid the above-mentioned precipitation in the gradually decreasing mode described in the application, in particular, is not the gradually decreasing mode of dripping arbitrarily selected The same effect can be achieved, as follows: the dropwise addition amount within 1min/the dropwise addition amount within the first 1min=90% or 95% dropwise addition, precipitation will inevitably occur, and the accompanying disadvantages also include inclusion rate reduction.

Further, the inclusion temperature in step 3) is 40-50°C, preferably 42°C; the inclusion time is 8-24h, preferably 12-16h.

Further, during the freeze-drying in step 4), the control pressure is less than 10 Pa, pre-freezing at -50--60°C for 4-6 hours, and then freeze-drying at -60--80°C for 24 hours.

Further, in the method for preparing the synergistic ingredient curcumin inclusion compound, the molar ratio of curcumin monophosphate and/or its salt to HP-β-CD is 1:2-5, preferably 1:3.0-3.5. The relationship between the degree of substitution (DS) of HP-β-CD and the average molecular weight (M) is shown in formulas (4) and (5).

D _s =[(∑H _i ×M _i /∑H _i )-1157]/58 (4)

M=D _S ×58+1135 (5)

In formulas (4) and (5), Hi and _Mi are the peak height and mass of the molecular ion peak _, respectively, 1135 is the molecular weight of β-CD, 1157 is the molecular weight of [β-CD+Na] ⁺ , and 58 is 1 the molecular weight of a hydroxypropyl group.

Further, in compound paracetamol granules, the mass ratio of acetaminophen, chlorpheniramine maleate, methylephedrine hydrochloride, curcumin inclusion complex and powdered sugar is 100～500:1:1～ 5:1～10:3000～10000.

Further, the powdered sugar is powdered sucrose, which passes through at least an 80-mesh screen after being pulverized.

Further, the compound paracetamol granules also include other adjuvant components, which specifically include:

The weight ratio of artificial bezoar to chlorpheniramine maleate is 1-10:1.

The binder, the weight ratio of which to chlorpheniramine maleate is 0.1 to 5.0:1, and the binder can be selected from gelatin, sodium carboxymethyl cellulose, povidone K30, and dextrin. one or more; and

Flavor, whose weight ratio to chlorpheniramine maleate is 0.2 to 1.0:1, and the flavor can be selected from one or more of steviol, aspartame, strawberry flavor, orange flavor, and hawthorn flavor .

[2] The preparation method of compound paracetamol granules described in item [1], specifically comprising:

A) preparing the curcumin inclusion compound;

B) adding appropriate amount of water to the inclusion complex of chlorpheniramine maleate and curcumin to make solution A;

C) acetaminophen, methylephedrine hydrochloride and powdered sugar are mixed and add an appropriate amount of water to make mucus B;

D) Add solution A to solution B and mix evenly, add or not add other auxiliary ingredients to make a soft material, which is obtained after granulation, drying and granulation.

The uniform mixing of the step D) can be achieved by the prior art such as stirring for at least 30 min.

The granulation in the step D) is granulated with a 20-40 mesh screen, preferably 40 mesh.

The drying in the step D) is drying to constant weight at a temperature of 45-60°C.

The granulation of the step D) is to granulate with a 10-40 mesh screen.

The preparation method is simple and feasible, and can be completed by using the current granulation process. The prepared compound paracetamol granules can be used in medicines for treating common cold or influenza, and the medicine effect is stable and reliable, even if chlorobenzene maleate Namin and methylephedrine hydrochloride can still maintain stable quality at ultra-low concentrations, thus ensuring the stable and efficient quality of the compound paracetamol granule composition, avoiding the side effects, adverse reactions and lower concentrations of the main drug at higher concentrations. The problem of reducing the stability of the efficacy and quality of the main drug.

[3] Use of the compound paracetamol granules according to any one of item [2] or [3] in the preparation of a medicine for preventing and/or treating a cold, wherein the cold is a common cold or an influenza.

The beneficial effects of the present invention are:

1) Inclusion of curcumin monophosphate and/or a mixture of HP-β-CD with a low degree of substitution (DS=5.4) and a high degree of substitution (DS=8.2) containing a specific molar ratio of HP-β-CD as a guest Its salt, the inclusion rate of the formed inclusion complex is significantly improved;

2) in a gradually decreasing manner, the ethanolic solution of curcumin monophosphate and/or its salt is added dropwise to HP-β-CD acid solution for inclusion, so that curcumin monophosphate and/or its salt can be improved to a greater extent. The inclusion rate of salt and HP-β-CD, and under the premise of no significant change in the color of curcumin monophosphate and/or its salt, the formed curcumin inclusion complexes are exposed to strong light, high temperature, and high humidity. The stability in different pH solutions is significantly higher than that of its corresponding curcumin monophosphate and/or its salt, and solubility and dissolution rate are also significantly improved. The quality of the sensitive particle composition is stable and efficient;

3) Cur-HP-β-CD inclusion compound formed by inclusion of curcumin monophosphate and/or its pharmaceutically acceptable salt with hydroxypropyl-β-cyclodextrin mixtures of different degrees of substitution as synergistic Ingredient, the bright yellow appearance of the Cur-HP-β-CD inclusion complex has exceptionally excellent optical hiding effect on chlorpheniramine maleate and methylephedrine hydrochloride, which can protect ultra-low concentrations of chlorpheniramine maleate Mining and methylephedrine hydrochloride are stable in quality, thereby ensuring the stable and efficient quality of the compound paracetamol granule composition, avoiding the side effects, adverse reactions, excessive problems of high-concentration methylephedrine hydrochloride and relatively high concentrations of the main drug. The problem of reducing the stability of the efficacy and quality of the main drug at low concentrations.

The present invention adopts the above-mentioned technical scheme to provide a sample document, makes up for the deficiencies of the prior art, has a reasonable design and is convenient to operate.

Description of drawings

In order to make the above and other objects, features, advantages and embodiments of the present invention more clearly understood, the accompanying drawings are described as follows:

Fig. 1 is the structural representation of hydroxypropyl-β-cyclodextrin of the present invention;

Fig. 2 is the schematic diagram of preparing inclusion complex with HP-β-CD inclusion guest molecule according to the present invention;

Fig. 3 is curcumin monophosphate structural representation of the present invention;

FIG. 4 is a schematic diagram of the inclusion rate statistics of curcumin inclusion compounds in the embodiment of the present invention.

Detailed ways

Unless otherwise defined, 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 employs the methods and materials described herein; however, other suitable methods and materials known in the art can also be used. The materials, methods, and examples described herein are illustrative only and not intended to be limiting. All publications, patent applications, patents, provisional applications, database entries, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control.

Unless otherwise stated, all percentages, parts, ratios, etc. are by weight, and "mol%" means mole percent.

As used herein, the term "produced by" is equivalent to "comprising". The terms "comprising", "comprising", "having", "having", "containing" or any other variation thereof as used herein are intended to encompass non-exclusive inclusion. For example, a composition, process, method, article or device comprising a series of elements is not necessarily limited to only those elements, but can also include elements not expressly recited or inherent in the composition, process, method, article or device other elements.

The conjunction "consisting of/consisting of" does not include any element, step or ingredient not expressly recited. If appearing in a claim, the conjunction will limit the claim to the recited materials to the exclusion of unrecited materials, but still to encompass impurities generally associated with those recited materials. When the conjunction "consists of/consists of" appears in the characterizing part of a claim, but not immediately before the preamble, it is limited to the elements stated in the characterizing part; other elements are not excluded from the claim as a whole .

The conjunction "consisting essentially of" is used to define combinations comprising additional materials, steps, features, components or elements in addition to those literally stated objects, methods, or apparatus, provided that such additional materials, steps, features, components or elements do not materially affect the essential and novel characteristics of the claimed invention. The term "consisting essentially of" is a middle ground between "comprising/comprising" and "consisting of/consisting of."

The term "comprising/comprising" is intended to include embodiments encompassed by the terms "consisting/consisting essentially of" and "consisting/consisting of." Similarly, the term "consisting/consisting essentially of" is intended to include embodiments encompassed by the term "consisting/consisting of."

When an amount, concentration, or other value or parameter is given in terms of a range, preferred range, or a series of upper and lower preferred values, it is to be understood that it specifically discloses the limitation or preference from any larger range and any smaller value All ranges formed by any pair of numerical values of the range limits or preferred values, whether or not the ranges are separately disclosed. For example, when describing the range of "1-5", the described range should be understood to include "1-4", "1-3", "1-2", "1-2 and 4-5", " 1 to 3 and 5" etc. range. Unless otherwise indicated, where numerical ranges are described herein, the ranges are intended to include the endpoints of the range as well as all integers and fractions within the range.

When the term "about" is used to describe a value or an endpoint of a range, the disclosure should be understood to include the specific value or endpoint referred to.

Furthermore, unless expressly stated to the contrary, "or (or)" refers to an inclusive "or (or)" rather than an exclusive "or (or)". For example, the condition A "or" B applies: A is true (or present) and B is false (or absent), A is false (or absent) and B is true (or present), and Both A and B are true (or exist).

Furthermore, the indefinite articles "a" and "an" preceding an element or component of the invention are intended to mean that the number of occurrences (ie, occurrences) of the element or component is not limiting. Thus "a" or "an" should be read to include one or at least one, and the singular form of said elements or components also includes the plural unless the number is expressly stated to be in the singular.

Embodiments of the invention, including the embodiments of the invention described in the Summary of the Invention and any other embodiments described herein below, may be arbitrarily combined, and descriptions of variables in the embodiments apply not only to the invention The compound paracetamol granules are also applicable to medicines prepared from the compound paracetamol granules.

Unless specifically stated, the materials, methods, and examples described herein are illustrative and not restrictive. 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.

Embodiment 1: a kind of compound paracetamol granule formula:

The present embodiment provides a compound paracetamol granule, comprising:

The main functional components are acetaminophen, chlorpheniramine maleate and methylephedrine hydrochloride;

A synergistic ingredient, which is a curcumin-type inclusion complex; and

Powdered sugar, which is crushed and passed through a 100-mesh sieve;

Wherein, the curcumin inclusion compound is a mixture containing 93.0mol% of HP-β-CD with DS=5.4 and 7.0mol% of HP-β-CD with DS=8.2 as the main body, and curcumin monophosphate The single lithium salt is the guest, and it is prepared by inclusion.

Said synergistic ingredient curcumin inclusion compound is prepared by the following steps:

1) Dissolve 40.40g DS=5.4 HP-β-CD and 3.38g DS=8.2 HP-β-CD in phosphoric acid with pH=2.0 to make 4.2wt% HP-β-CD acid solution;

2) 4.47g of curcumin monophosphate monolithium salts were added with a large amount of dehydrated alcohol to dissolve;

3) Under the constant temperature of 42°C and the stable rotation speed of 120r/min, the ethanol solution of curcumin monophosphate monolithium salt was added dropwise to the HP-β-CD acid solution in a gradually decreasing manner within 15min, and the Enter nitrogen and seal, and continue to stir and seal for 12h in the dark;

4) After equilibration, the suspension was centrifuged at a high speed of 24,000 r/min, and the supernatant was collected and lyophilized.

In step 3), dripping in a gradually decreasing manner means that the relationship between the dripping amount V _i in the ith min and the dripping amount V ₁ in the 1st min conforms to formula (3): V _i =V ₁ ×[( 102-2i)]% (3), wherein i is an integer between 1 and 15; that is, the dripping volume V2 of the _2nd min is 98% of the dripping volume V1 of the _1st min, and the dripping volume of the 3rd min is 98%. The amount _V3 is 96% of the dripping amount V1 in the _1st min, the dripping amount V4 in the _4th min is 94% of the dripping amount V1 in the _1st min, ..., the dripping amount V15 until the _15th min is the 1min dripping amount V15 72% of the dripping amount V ₁ , the value of V ₁ can be calculated according to the total amount, and the values of V ₂ , V ₃ , V ₄ , ..., V ₁₅ can be calculated, and can be completed according to each dripping amount dropwise.

During the freeze-drying in step 4), the pressure was controlled at 8 Pa, pre-freezing at -55°C for 4.5 hours, and then freeze-drying at -80°C for 24 hours.

This embodiment also provides the preparation method of the above-mentioned compound paracetamol granules, which specifically includes:

A) preparing the curcumin inclusion compound;

B) in 1.0g chlorpheniramine maleate and 5.0g curcumin inclusion compound, add appropriate amount of water to make solution A;

C) 140g of acetaminophen, 1.2g of methylephedrine hydrochloride and 5500g of powdered sugar are mixed and added an appropriate amount of water to make mucus B;

D) Add solution A to solution B and mix evenly, add 3.0 g of artificial bezoar, 0.4 g of carboxymethyl cellulose and 0.8 g of steviol and mix evenly to make a soft material, which is granulated, dried and granulated.

Specifically, the above-mentioned preparation method also includes the limitations listed in the following (a) to (g):

(a) Step A) preparing the curcumin inclusion compound is prepared according to the specific preparation steps of the present embodiment;

(b) the appropriate amount of water of step B) is 200g;

(c) the appropriate amount of water of step C) is 3500g;

(d) the uniform mixing of step C) and step D) is to stir and mix uniformly under the conditions of 120r/min and 30min;

(e) the granulation of step D) is to granulate with 40 mesh screen;

(f) The drying of step D) is drying to constant weight at a temperature of 52°C;

(g) The granulation of step D) is granulated with a 30-mesh sieve.

Example 2: Another formula of compound paracetamol granules:

The formula of compound paracetamol granules in this example and the preparation method thereof are basically the same as those in Example 1, the difference is that in this example, when preparing the synergistic ingredient curcumin-type inclusion compound, the compound with DS=5.4 was used. The addition amount of HP-β-CD is 40.40g, and the addition amount of HP-β-CD with DS=4.2 is 2.90g, that is, the moles of HP-β-CD with DS=5.4 and HP-β-CD with DS=4.2 The ratio is 93.0:7.0. The proportions of the remaining components and the preparation process are the same as those in Example 1, and compound paracetamol granules are finally prepared.

Example 3: Another formula of compound paracetamol granules:

The formula of compound paracetamol granules in this example and the preparation method thereof are basically the same as those in Example 1, the difference is that in this example, when preparing the synergistic component curcumin-type inclusion compound, the compound with DS=7.4 was used. The addition amount of HP-β-CD is 43.64g, and the addition amount of HP-β-CD with DS=8.2 is 3.38g, that is, the moles of HP-β-CD with DS=7.4 and HP-β-CD with DS=4.2 The ratio is 93.0:7.0. The proportions of the remaining components and the preparation process are the same as those in Example 1, and compound paracetamol granules are finally prepared.

Example 4: Another formula of compound paracetamol granules:

The formula and preparation method of compound paracetamol granules in this example are basically the same as those in Example 1, except that in this example, when preparing the synergistic ingredient curcumin-type inclusion complex, the HP of DS=5.4 - The addition amount of β-CD is 21.72g, and the addition amount of HP-β-CD with DS=8.2 is 24.16g, that is, the molar ratio of HP-β-CD with DS=5.4 and HP-β-CD with DS=8.2 is 1:1. The proportions of the remaining components and the preparation process are the same as those in Example 1, and compound paracetamol granules are finally prepared.

Example 5: Another formula of compound paracetamol granules:

The formula and preparation method of compound paracetamol granules in this example are basically the same as those in Example 1, except that in this example, when preparing the synergistic ingredient curcumin-type inclusion complex, the HP of DS=5.4 - The addition amount of β-CD is 3.04g, and the addition amount of HP-β-CD with DS=8.2 is 44.94g, that is, the molar ratio of HP-β-CD with DS=5.4 and HP-β-CD with DS=8.2 is 7.0:93.0. The proportions of the remaining components and the preparation process are the same as those in Example 1, and compound paracetamol granules are finally prepared.

Example 6: Another formula of compound paracetamol granules:

The formula and preparation method of compound paracetamol granules in this example are basically the same as those in Example 1, except that in this example, when preparing the synergistic ingredient curcumin-type inclusion complex, the HP of DS=5.4 - The addition amount of β-CD is 43.45g, and the addition amount of HP-β-CD with DS=8.2 is 0g, that is, the HP-β-CD in the preparation of curcumin inclusion complex is changed from a single HP-β-CD with DS=5.4 -CD composition. The proportions of other components and the preparation process are the same as those in Example 1, and compound paracetamol granules are finally prepared.

Example 7: Another formula of compound paracetamol granules:

The formula and preparation method of compound paracetamol granules in this example are basically the same as those in Example 1, except that in this example, when preparing the synergistic ingredient curcumin-type inclusion complex, the HP of DS=5.4 - The addition amount of β-CD is 0g, and the addition amount of HP-β-CD with DS=8.2 is 48.32g, that is, the HP-β-CD in the preparation of curcumin-type inclusion complex is changed from a single HP-β-CD with DS=8.2 -CD composition. The proportions of other components and the preparation process are the same as those in Example 1, and compound paracetamol granules are finally prepared.

Embodiment 8: another kind of compound paracetamol granule formula:

The formula of compound paracetamol granules in this example and the preparation method thereof are basically the same as those in Example 1, the difference is that in this example, when preparing the synergistic ingredient curcumin-type inclusion compound, step 3) described The dripping in a gradually decreasing manner specifically refers to: the dripping amount in the last 1min is 95% of the dripping amount in the first 1min, that is to say, the dripping amount V2 of the _2nd min is the dripping amount V1 of the _1st min. 95% of the dripping amount V3 in the ₃ min is 95% of the dripping amount V2 in the ₂ min, the dripping amount V4 in the ₄ min is 95% of the dripping amount V3 in the ₃ min, ... until the 15min The dripping amount V ₁₅ is 95% of the dripping amount V ₁₄ in the 14th min. According to the total amount, the value of V ₁ can be calculated, and the value of V ₂ , V ₃ , V ₄ , ..., V ₁₅ can be calculated. , and the dripping can be completed according to each dripping amount, and trace crystals are precipitated during the process. The proportions of other components and the preparation process are the same as those in Example 1, and compound paracetamol granules are finally prepared.

Embodiment 9: another kind of compound paracetamol granule formula:

The formula of compound paracetamol granules in this example and the preparation method thereof are basically the same as those in Example 1, the difference is that in this example, when preparing the synergistic ingredient curcumin-type inclusion compound, step 3) described The dripping method is carried out in a way of measuring each dripping, specifically: the dripping amounts V ₁ , V ₂ , V ₃ , V ₄ , ..., V ₁₅ in each minute are equal, all of which are curcumin monophosphate. It is 1/15 of the total amount of the ethanol solution of the ester monolithium salt, and can be added dropwise according to each dropwise amount, and a small amount of crystals are precipitated during the process. The proportions of other components and the preparation process are the same as those in Example 1, and compound paracetamol granules are finally prepared.

Embodiment 10: Another compound paracetamol granule formula:

The formula of compound paracetamol granules in this example and the preparation method thereof are basically the same as those in Example 1, the difference is that in this example, when preparing the synergistic ingredient curcumin-type inclusion compound, step 3) described The dripping is carried out in a gradually increasing manner, specifically: the dripping amount in the last 1min is 105% of the dripping amount in the first 1min, that is to say, the dripping amount V of the _2nd min is the dripping amount V of the 1st min. 105% of ₁ , the dripping volume V3 of the _3rd min is 105% of the dripping volume V2 of the _2nd min, the dripping volume V4 of the _4th min is 105% of the dripping volume V3 of the _3rd min, ... until the th The dripping amount V ₁₅ in 15min is 105% of the dripping amount V ₁₄ in the 14th min. According to the total amount, the value of V ₁ can be calculated, and the values of V ₂ , V ₃ , V ₄ , ..., V ₁₅ can be calculated. value, and the dropwise addition can be completed according to each dropwise amount, and a large amount of crystals are precipitated during the process. The proportions of other components and the preparation process are the same as those in Example 1, and compound paracetamol granules are finally prepared.

Embodiment 11: another compound paracetamol granule formula:

The formula of compound paracetamol granules in this embodiment and the preparation method thereof are basically the same as those in Example 1, the difference is that in this embodiment, when compounding and preparing compound paracetamol granules, the curcumin inclusion compound The addition amount is 0.1 g. The proportions of other components and the preparation process are the same as those in Example 1, and compound paracetamol granules are finally prepared.

Embodiment 12: another compound paracetamol granule formula:

The formula of compound paracetamol granules in this embodiment and the preparation method thereof are basically the same as those in Example 1, the difference is that in this embodiment, when compounding and preparing compound paracetamol granules, the curcumin inclusion compound The added amount is 0 g. The proportions of other components and the preparation process are the same as those in Example 1, and compound paracetamol granules are finally prepared.

Embodiment 13: another compound paracetamol granule formula:

The formula of compound paracetamol granules in this embodiment and the preparation method thereof are basically the same as those in Example 1, except that in this embodiment, when compounding and preparing compound paracetamol granules, the addition of methylephedrine hydrochloride The amount is 0g. The proportions of other components and the preparation process are the same as those in Example 1, and compound paracetamol granules are finally prepared.

Embodiment 14: another compound paracetamol granule formula:

The formula of compound paracetamol granules in this embodiment and the preparation method thereof are basically the same as those in Example 1, except that in this embodiment, when compounding and preparing compound paracetamol granules, the addition of methylephedrine hydrochloride The amount is 0.1 g. The proportions of other components and the preparation process are the same as those in Example 1, and compound paracetamol granules are finally prepared.

Experimental Example 1: Detection of the inclusion rate of curcumin inclusion compounds:

Accurately weigh an appropriate amount of the lyophilized product of curcumin inclusion complexes, add a small amount of anhydrous ethanol and sonicate for 20min, transfer to a 100mL brown volumetric flask after the end, add anhydrous ethanol to dilute to the mark, use anhydrous ethanol as a blank, at a wavelength of 423nm Measure the absorbance of the inclusion compound at the place, obtain the content of curcumin in the inclusion compound according to the regression equation, and calculate the inclusion rate according to formula (6):

Inclusion rate = (C _E /C _T )×100% (6)

In formula (6), _CE is the weight of the incorporated curcuminoids measured by UV spectrophotometry at a wavelength of 423 nm, and _CT is the total weight of the curcuminoids initially added.

According to the method of this experimental example, the inclusion rate of the curcumin-type inclusion compounds in Examples 1 to 10 was detected, and the statistical data are shown in Figure 4. It can be seen from the diagram in FIG. 4 that the inclusion rate of curcumin-type inclusion compounds in the preferred embodiment 1 of the present application is the highest, exceeding 95%, while the remaining embodiments, whether it is HP-β- CD mixture, HP-β-CD mixture with high degree of substitution, or a single HP-β-CD with high or low degree of substitution, or a mixture of HP-β-CD with varying degree of substitution as the inclusion guest, or turmeric The ethanol solution of monophosphate and/or its salt is added dropwise to HP-β-CD acid solution in a measured, gradually increasing or gradually decreasing manner different from the decreasing manner described in this application, and the prepared curcuminoids The inclusion rates of the inclusion complexes all decreased significantly, and it can be deduced that the bioavailability will decrease.

Example 2: Detection of physicochemical properties of compound paracetamol granules:

A. Character detection:

According to the sampling method stipulated in the National Pharmacopoeia, the particles in Examples 1 to 14 were sampled respectively, and 5 samples were taken from each example, and the color and luster were checked and the statistical results are shown in Table 1. The above-mentioned inspection results show that, according to the compound paracetamol granules obtained by the present invention, all the properties of the granules meet the requirements of the national standard.

Table 1. Properties of Compound Paracetamol Granules

B. Solubility test:

According to the sampling method stipulated in the National Pharmacopoeia, the compound paracetamol granules in Examples 1 to 14 of the present application were sampled, 5 samples were taken from each example, and 10 g of each sample was sampled for solubility inspection. The solubility inspection method under the Pharmacopoeia (2015 edition four parts) granules is checked, and the inspection results show that all the compound paracetamol granules in Examples 1 to 14 of the application are qualified, indicating the formulation of the application and the process parameters. The setting is reasonable.

C, chlorpheniramine maleate content detection:

According to the sampling method stipulated in the National Pharmacopoeia, all the compound paracetamol granules in Examples 1 to 14 of the present application were sampled respectively, and 5 samples were taken from each example, and the high-performance liquid Chromatography detects the content of chlorpheniramine maleate, and its detection results are shown in Table 2.

Table 2. Chlorpheniramine maleate content

As can be seen from Table 2, the curcumin class inclusion compound of high inclusion rate in the application has a positive effect on the maintenance of ultra-low-content chlorpheniramine maleate efficacy, thereby ensuring compound paracetamol granules The composition quality is stable and efficient.

D, content detection of methylephedrine hydrochloride:

According to the sampling method stipulated in the National Pharmacopoeia, all the compound paracetamol granules in Examples 1 to 14 of the application were sampled respectively, and 5 samples were taken from each example, and the methyl hydrochloride was detected according to the Chinese Pharmacopoeia (2015 Edition Four) base ephedrine, and its detection results are shown in Table 3.

Table 3, methylephedrine hydrochloride content

As can be seen from Table 3, the curcumin class inclusion compound of high inclusion rate in the application has a positive effect on the maintenance of ultra-low-content methylephedrine hydrochloride efficacy, thereby ensuring the compound paracetamol granule composition Stable quality and high efficiency, in addition, as can be seen from the data in Example 14, the methylephedrine hydrochloride of ultra-low dosage content is more prone to failure.

The conventional technology in the above-mentioned embodiment is the prior art known to those skilled in the art, so it will not be described in detail here.

While the foregoing detailed description has shown, described and indicated novel features applicable to the various embodiments, it should be understood that changes may be made in the form and detail of the illustrated apparatus or method without departing from the spirit of the present disclosure. Various omissions, substitutions and changes. Additionally, the various features and methods described above may be used independently of each other or in various combinations. All possible combinations and subcombinations are intended to fall within the scope of this disclosure. Many of the above-described embodiments include similar components, and thus, these similar components are interchangeable in different embodiments. While the present invention has been disclosed in the context of certain embodiments and examples, it will be understood by those skilled in the art that the present invention extends beyond the specifically disclosed embodiments to other alternative embodiments and/or applications as well as their obvious Modifications and Equivalents. Therefore, it is not intended that the present invention be limited by the specific disclosure of the preferred embodiments herein.

Claims (8)

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;

wherein in the compound paracetamol and chlorphenamine maleate granules, the mass ratio of the acetaminophen, the chlorphenamine maleate, the methylephedrine hydrochloride, the curcumin clathrate to the powdered sugar is 100-500: 1: 1-5: 1-10: 3000-10000;

the curcumin clathrate compound is prepared by taking hydroxypropyl-beta-cyclodextrin mixture with different degrees of substitution as a main body and taking curcumin monophosphate and/or salt thereof as an object;

the hydroxypropyl-beta-cyclodextrin mixture having different degrees of substitution comprises:

hydroxypropyl-beta-cyclodextrin with a DS of 93.0 mol% 5.4, and

hydroxypropyl- β -cyclodextrin with 7.0 mol% DS ═ 8.2.

2. A compound paracetamol and chlorpheniramine maleate particle according to claim 1 wherein: the curcumin monophosphate and/or the salt thereof comprises: curcumin monophosphate, and mono-or di-salts of curcumin monophosphate.

3. A compound paracetamol particle according to claim 1 or 2, wherein: the curcumin clathrate compound as the synergistic component is prepared by the following steps:

1) dissolving hydroxypropyl-beta-cyclodextrin in an acid solution with the pH value of 2.0 to prepare 4.0-5.0 wt% of hydroxypropyl-beta-cyclodextrin 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 hydroxypropyl-beta-cyclodextrin 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.

4. A compound paracetamol and chlorpheniramine maleate particle according to claim 3 wherein: the step 3) of dropwise adding in a gradually decreasing manner refers to the dropwise adding amount V in the ith min _i And the dropping amount V in the 1 st min ₁ The relationship (2) corresponds to the formula (3):

V _i ＝ ₁ ×[(102-2i)]％(3)，

in the formula (3), i is 1 to i _max I is 10. ltoreq. i _max ≤20。

5. A compound paracetamol and chlorpheniramine maleate particle according to claim 3 wherein: and 4) during freeze-drying, controlling the pressure to be less than 10Pa, pre-freezing for 4-6 h at the temperature of-50 to-60 ℃, and then freeze-drying for 24h at the temperature of-60 to-80 ℃.

6. A compound paracetamol particle according to any one of claims 1, 2, 4 and 5, wherein: the compound paracetamol and chlorphenamine maleate granules also comprise other auxiliary material components, and specifically comprise the following components:

artificial bezoar, wherein the weight ratio of the artificial bezoar to the chlorphenamine maleate is 1-10: 1;

the weight ratio of the adhesive to the chlorpheniramine maleate is 0.1-5.0: 1, and the adhesive is selected from one or more of gelatin, sodium carboxymethylcellulose, povidone K30 and dextrin; and

the weight ratio of the essence to the chlorphenamine maleate is 0.2-1.0: 1, and the essence is selected from one or more of strawberry essence, orange essence and hawthorn essence.

7. A process for preparing the compound paracetamol and chlorpheniramine maleate granules according to any one of claims 1 to 6, 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, making into soft material, granulating, drying and finishing.

8. Use of the compound paracetamol and chlorpheniramine maleate granules according to any one of claims 1 to 6 for the preparation of a medicament for the prevention and/or treatment of cold, wherein the cold is common cold or influenza.

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