Pharmaceutical compositions comprising a combination of a compound of formula (I) and a compound of formula (II)

Abstract

The application discloses a compound solid preparation containing phenylephrine hydrochloride and a preparation method thereof, which is a solid preparation prepared by taking phenylephrine hydrochloride, acetaminophen and chlorpheniramine maleate as active ingredients, and taking a coating agent, a binder, a filler, a lubricant and the like as auxiliary materials, and the solid preparation is a tablet. Since phenylephrine hydrochloride can be degraded in the presence of oxygen, aldehyde, certain acids and metals, the phenylephrine hydrochloride is coated with a coating agent, and then mixed with other raw and auxiliary materials to prepare granules by using a dry granulation method, and finally, the granules are compressed to obtain the tablet.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical preparation technology, specifically relating to a compound solid dosage form containing phenylephrine hydrochloride and its preparation method. Background Technology

[0002] Phenylephrine hydrochloride is an α-adrenergic receptor agonist with vasoconstrictive and blood pressure-raising effects. It is a potent vasoconstrictor and is used as a nasal decongestant and cardiac agonist. Phenylephrine also causes pulmonary vasoconstriction, followed by an increase in pulmonary artery pressure and vasoconstriction in the respiratory tract mucosa. It is often combined with antihistamines, expectorants, antitussives, and antipyretics to treat symptoms such as fever, nasal congestion, runny nose, cough, sneezing, or headache caused by the common cold.

[0003] Acetaminophen, also known as paracetamol, is a metabolite of phenacetin. It works by inhibiting prostaglandin synthase in the hypothalamic thermoregulatory center, reducing the synthesis and release of prostaglandins such as PGE1, bradykinin, and histamine. It is an antipyretic and analgesic, with a stronger antipyretic effect than analgesic effect.

[0004] Chlorpheniramine maleate, also known as Chlorpheniramine, is an antihistamine that works by antagonizing H1 receptors. It is primarily used for rhinitis, skin and mucous membrane allergies, and to relieve cold symptoms such as tearing, sneezing, and runny nose.

[0005] The combination of the above three medications can relieve symptoms such as fever, headache, cough and nasal congestion caused by the common cold. Summary of the Invention

[0006] Brief description of the invention:

[0007] This invention relates to a compound solid dosage form containing phenylephrine hydrochloride and its preparation method. The solid dosage form is prepared by using phenylephrine hydrochloride (an α-adrenergic receptor agonist), acetaminophen (an antipyretic analgesic), and chlorpheniramine maleate (an antihistamine) as active ingredients, along with excipients such as encapsulating agents, binders, fillers, and lubricants. The solid dosage form is a tablet.

[0008] Because phenylephrine hydrochloride can degrade in the presence of oxygen, aldehydes, certain acids and metals, this invention first encapsulates phenylephrine hydrochloride with an encapsulating agent, then granulates it using a dry granulation method, and finally mixes it with granules prepared from other raw materials and excipients, and compresses it into tablets.

[0009] Detailed description of the invention:

[0010] This invention relates to tablets prepared using both dry and wet granulation methods. First, phenylephrine hydrochloride is encapsulated with an encapsulating agent, then pulverized, dry-granulated, and sized. Acetaminophen and chlorpheniramine maleate are pulverized into fine powders, mixed with pulverized fillers, and then formed into a soft mass using a binder. After granulation, drying, and sizing, the sized phenylephrine hydrochloride granules and a lubricant are added. After mixing and compression, the tablets are obtained.

[0011] To further stabilize norepinephrine hydrochloride, an antioxidant was also added to this invention.

[0012] Unless otherwise specified, all weights mentioned herein are for the active pharmaceutical ingredient in the composition and the excipients required for tablet preparation at 18-25°C.

[0013] Unless otherwise specified, all percentages herein are by weight and all percentages are based on the total composition.

[0014] The embodiments of this invention disclose a variety of implementation schemes, all of which are feasible for those skilled in the art, and some are preferred.

[0015] The specific technical solution for implementing the present invention is as follows:

[0016] A compound solid dosage form containing norepinephrine hydrochloride and its preparation method thereof, characterized in that it comprises the following components by weight percentage:

[0017] Acetaminophen 30-60%; Chlorpheniramine maleate 0-0.5%; Norepinephrine hydrochloride 0-0.6%; Filler 30-55%; Encapsulating agent 0-10%; Adhesive 2-10%; Antioxidant 1-5%; Lubricant 0-0.5%.

[0018] The compound solid dosage form of dephenylephrine hydrochloride and its preparation method as described above are characterized by comprising the following components by weight percentage:

[0019] Acetylchlorophenol 32.5%; Chlorpheniramine maleate 0.2%; Norepinephrine hydrochloride 0.5%; Filler 47%; Encapsulating agent 8%; Adhesive 8%; Antioxidant 3.5%; Lubricant 0.3%.

[0020] The compound solid dosage form of dephenylephrine hydrochloride and its preparation method as described above are characterized by comprising the following components by weight percentage:

[0021] Acetaminophen 32.5%; Chlorpheniramine maleate 0.4%; Norepinephrine hydrochloride 0.4%; Filler 48%; Encapsulating agent 7%; Adhesive 8%; Antioxidant 3.3%; Lubricant 0.4%.

[0022] The compound solid dosage form of dephenylephrine hydrochloride and its preparation method as described above are characterized by comprising the following components by weight percentage:

[0023] Acetaminophen 50.0%; Chlorpheniramine maleate 0.2%; Norepinephrine hydrochloride 0.2%; Filler 35%; Encapsulating agent 5.3%; Adhesive 6%; Antioxidant 3%; Lubricant 0.3%.

[0024] In any of the components described above, the filler includes, but is not limited to, one or a mixture of two or more of lactose, sucrose, glucose, and starch.

[0025] In any of the components described above, the encapsulating agent includes, but is not limited to, one or a mixture of more than one of PEG4000, PEG6000, or PEG8000, preferably a mixture of PEG4000 and PEG6000, with a mixing ratio of PEG4000:PEG6000 = 3:1. In any of the components described above, the adhesive includes, but is not limited to, one or a mixture of two or more of PVP, carboxymethyl cellulose, and povidone. When using, the adhesive should be soaked in cool water for 10-18 hours before use.

[0026] In any of the components described above, the antioxidant includes, but is not limited to, one or a mixture of two or more of vitamin C, sodium metabisulfite, and propyl gallate.

[0027] In any of the components described above, the lubricant includes, but is not limited to, micronized silica gel, talc, or magnesium stearate.

[0028] The compound solid dosage form of norepinephrine hydrochloride described above and its preparation method are as follows:

[0029] a. After heating the encapsulating agent in the component to 55-70℃ and melting it, add phenylephrine hydrochloride while stirring. Stir evenly, cool, crush, sieve, dry granulate, and granulate to obtain granule 1 for later use.

[0030] b. Mix the acetaminophen, chlorpheniramine maleate, filler, and antioxidant in the components evenly, add the binder to make a soft mass, granulate, dry, and granulate to obtain granules 2 for later use.

[0031] c. Place the above-mentioned particles 1 and 2 in a mixer, add lubricant and mix evenly, then compress into tablets to obtain the final product.

[0032] The sieving mentioned in section a refers to sieving through a 100-120 mesh sieve.

[0033] The dry granulation method mentioned in section a refers to granulation using a dry granulation machine, where the mesh size of the sieve used for granulation is 18-24 mesh.

[0034] The granulation mentioned in section a refers to granulation using an 18-24 mesh sieve.

[0035] The granulation mentioned in b refers to granulation using a 20-24 mesh sieve.

[0036] The drying described in b refers to a drying temperature of 50-70℃;

[0037] The granulation mentioned in b refers to granulation using a 20-24 mesh sieve.

[0038] The mixing mentioned in c refers to mixing with a mixer for 30-60 minutes.

[0039] Beneficial effects

[0040] This invention relates to a compound solid dosage form containing phenylephrine hydrochloride and its preparation method. The active ingredients are phenylephrine hydrochloride (an α-adrenergic receptor agonist), acetaminophen (an antipyretic analgesic), and chlorpheniramine maleate (an antihistamine), combined with excipients such as encapsulating agents, binders, fillers, and lubricants. The solid dosage form is a tablet.

[0041] In this invention, since phenylephrine hydrochloride can degrade in the presence of oxygen, aldehydes, certain acids and metals, the phenylephrine hydrochloride is first encapsulated with an encapsulating agent before granulation. To prevent the drug from being oxidized and degraded, an antioxidant is added during the preparation process. Detailed Implementation

[0042] The following embodiments further describe and demonstrate implementation schemes within the scope of the present invention. These embodiments are given for illustrative purposes only and should not be construed as limiting the present invention.

[0043] Example 1

[0044] Formula composition: Acetaminophen 32.5%; Chlorpheniramine maleate 0.2%; Norepinephrine hydrochloride 0.5%; Sucrose 47%; PEG 4000 6%; PEG 6000 2%; Povidone K 30 8%; Sodium metabisulfite 3.5%; Magnesium stearate 0.3%.

[0045] Preparation method

[0046] 1. Melt PEG4000 and PEG6000 in the components at 55-70℃, add phenylephrine hydrochloride while stirring, stir evenly, cool, pulverize, sieve through a 100-mesh sieve, dry granulate through a 20-mesh sieve, and granulate through a 24-mesh sieve to obtain granules 1, for later use.

[0047] 2. Mix acetaminophen, chlorpheniramine maleate, sucrose, and sodium metabisulfite evenly, add povidone K30 to make a soft mass, granulate through a 24-mesh sieve, dry at 55-60℃, and granulate through a 24-mesh sieve to obtain granules 2, which are ready for use.

[0048] 3. Place the above-mentioned particles 1 and 2 in a mixer, add magnesium stearate, mix evenly, and compress into tablets to obtain the final product.

[0049] Example 2

[0050] Formula composition: Acetaminophen 32.5%; Chlorpheniramine maleate 0.4%; Norepinephrine hydrochloride 0.4%; Starch 48%; PEG 6000 7%; PVP 8%; Vitamin C 3.3%; Micronized silica gel 0.4%.

[0051] Preparation method

[0052] 1. Melt PEG6000 in the component at 55-70℃, add dephenylephrine hydrochloride while stirring, stir evenly, cool, pulverize, sieve through a 100-mesh sieve, dry granulate through an 18-mesh sieve, and granulate through a 24-mesh sieve to obtain granules 1, for later use.

[0053] 2. Mix acetaminophen, chlorpheniramine maleate, sucrose, and vitamin C evenly, add starch to make a soft mass, granulate through a 24-mesh sieve, dry at 55-60℃, and granulate through a 24-mesh sieve to obtain granules 2, which are ready for use.

[0054] 3. Place the above particles 1 and 2 in a mixer, add the micronized silica gel, mix evenly, and compress into tablets to obtain the final product.

[0055] Example 3

[0056] Prescription composition

[0057] Acetaminophen 32.5%; Chlorpheniramine maleate 0.2%; Norepinephrine hydrochloride 0.5%; Sucrose 47%; PEG4000 8%; PVP 8%; Sodium metabisulfite 3.5%; Magnesium stearate 0.3%.

[0058] Its preparation method:

[0059] 1. After melting PEG4000 in the component at 55-70℃, add dephenylephrine hydrochloride while stirring, stir evenly, cool, pulverize, sieve through a 120-mesh sieve, dry granulate, and granulate through a 24-mesh sieve to obtain granules 1 for later use.

[0060] d. Mix acetaminophen, chlorpheniramine maleate, sucrose, and sodium metabisulfite evenly, add PVP to make a soft material, granulate through a 24-mesh sieve, dry at 60℃, and granulate through a 24-mesh sieve to obtain granules 2, which are ready for use.

[0061] e. Place the above particles 1 and 2 in a mixer, add magnesium stearate, mix evenly, and compress into tablets to obtain the final product.

[0062] Example 4 (Stability Test)

[0063] The stability of the invention was further investigated using high temperature, high humidity, and light exposure tests.

[0064] Experimental Method: Ten samples prepared in Example 1, each containing 10 tablets, were placed in sealed bags and sealed. These were divided into 10 groups of 10 tablets each. The groups were then placed under high temperature (60℃), high humidity (95% ± 2%), and light (4500 Lx ± 500 Lx) conditions for 60 days. The levels of acetaminophen (A), chlorpheniramine maleate (B), and norepinephrine hydrochloride (C) were used as detection indicators. Samples were taken on days 10 and 60 for testing. The results are shown in Table 1.

[0065] Table 1: Sample Testing Results under High Temperature, High Humidity, and Light Conditions

[0066]

[0067] Experiments show that the content of acetaminophen, chlorpheniramine maleate, and phenylephrine hydrochloride in the above product decreases significantly under high temperature conditions. Under strong light and high humidity conditions, the changes in the active ingredients are not significant, indicating that except for instability under high temperature conditions, other storage conditions do not significantly alter the invention. Therefore, the invention is not suitable for storage under high temperature conditions.

Claims

1. A combined solid preparation containing phenylephrine hydrochloride, characterized in that It is made from the following components by weight percentage: acetaminophen 30-60%, chlorpheniramine maleate 0.2-0.5%, norepinephrine hydrochloride 0.2-0.6%, filler 30-55%, encapsulating agent 5.3-10%, binder 2-10%, antioxidant 1-5%, lubricant 0.3-0.5%; The encapsulating agent is at least one of PEG4000 or PEG6000; The antioxidant is vitamin C or sodium metabisulfite; The preparation method of the compound solid dosage form containing phenylephrine hydrochloride is as follows: (1) After heating the coating agent in the component to melt at 55-70℃, add hydrochloric acid dephenylephrine while stirring, stir evenly, cool, crush, sieve, dry granulate, and granulate to obtain granules 1 for later use. (2) Mix the acetaminophen, chlorpheniramine maleate and filler and antioxidant in the components evenly, add binder to make soft material, granulate, dry, and granulate to obtain granules 2 for later use; (3) Place the above particles 1 and 2 in a mixer, add lubricant and mix evenly, then compress into tablets to obtain the product.

2. The compound solid preparation containing phenylephrine hydrochloride according to claim 1, characterized by It is made by weight percentage of the following components: acetaminophen 32.5%, chlorpheniramine maleate 0.2%, norepinephrine hydrochloride 0.5%, filler 47%, encapsulating agent 8%, adhesive 8%, antioxidant 3.5%, and lubricant 0.3%.

3. The compound solid preparation containing phenylephrine hydrochloride according to claim 1, characterized by It is made by weight percentage of the following components: acetaminophen 32.5%, chlorpheniramine maleate 0.4%, norepinephrine hydrochloride 0.4%, filler 48%, encapsulating agent 7%, binder 8%, antioxidant 3.3%, and lubricant 0.4%.

4. The compound solid preparation containing phenylephrine hydrochloride according to claim 1, characterized by It is made by weight percentage of the following components: acetaminophen 50.0%, chlorpheniramine maleate 0.2%, norepinephrine hydrochloride 0.2%, filler 35%, encapsulating agent 5.3%, binder 6%, antioxidant 3%, and lubricant 0.3%.

5. The compound solid preparation containing phenylephrine hydrochloride according to any one of claims 1 to 4, characterized by The fillers include, but are not limited to, lactose, sucrose, glucose, or starch.

6. The compound solid preparation containing phenylephrine hydrochloride according to any one of claims 1 to 4, characterized by The adhesive includes, but is not limited to, PVP or carboxymethyl cellulose. When using the adhesive, soak it in cool water for 10-18 hours before use.

7. The compound solid dosage form containing phenylephrine hydrochloride according to any one of claims 1-4, characterized in that... The lubricant includes, but is not limited to, micronized silica gel, talc, or magnesium stearate.

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