CN112618505B

CN112618505B - Compound pharmaceutical composition containing benazepril and pimobendan for pets and preparation method thereof

Info

Publication number: CN112618505B
Application number: CN202011604817.1A
Authority: CN
Inventors: 刘利锋; 朱玉玲; 朱成强
Original assignee: Nanjing Langbote Animal Pharmaceutical Co ltd
Current assignee: Nanjing Langbote Animal Pharmaceutical Co ltd
Priority date: 2020-12-30
Filing date: 2020-12-30
Publication date: 2022-11-15
Anticipated expiration: 2040-12-30
Also published as: CN112618505A

Abstract

The invention relates to the technical field of pharmaceutical compositions, in particular to a compound pharmaceutical composition containing benazepril and pimobendan for pets and a preparation method thereof; the pharmaceutical composition comprises the following raw material medicines in percentage by weight: 1 to 8.0 percent of benazepril hydrochloride, 0.5 to 4.0 percent of pimobendan, 42 to 71 percent of diluent, 1 to 5 percent of slow release framework, 10 to 20 percent of coating taste masking material, 1.5 to 4 percent of disintegrating agent, 1 to 5 percent of adhesive, 5 to 15 percent of solubilizer, 1 to 5 percent of glidant, 1 to 3 percent of lubricant, 0.5 to 2 percent of flavoring agent and a small amount of pigment; the compound composition prepared by the invention has the characteristics of convenient administration, lasting effect and stable curative effect, can relax blood vessels and reduce blood pressure so as to relieve cardiac burden, and can increase myocardial contractility and improve the survival rate of sick dogs; the medicine has fast effect and high bioavailability; and because of adding the taste-masking coating process and a proper amount of meat flavor corrective, the pet-friendly taste is provided, so that the animal compliance is greatly improved.

Description

Compound pharmaceutical composition containing benazepril and pimobendan for pets and preparation method thereof

Technical Field

The invention relates to the technical field of pharmaceutical compositions, in particular to a compound pharmaceutical composition containing benazepril and pimobendan for pets and a preparation method thereof.

Background

Benazepril hydrochloride (benazepril hydrochloride) is a prodrug that is hydrolyzed in the liver to the active metabolite benazeprilat. The latter is a thiol-free Angiotensin Converting Enzyme (ACE) inhibitor, which inhibits the conversion of angiotensin I to angiotensin II, resulting in reduced vascular resistance, reduced aldosterone secretion, and increased plasma renin-activating renin activity. Can also inhibit the degradation of bradykinin, reduce vascular resistance, and lower blood pressure. Benazepril can dilate arteries and veins during heart failure, reduce peripheral vascular resistance (afterload) and pulmonary capillary wedge pressure (preload), thereby improving cardiac output and improving exercise tolerance of patients, and can be used for treating congestive heart failure.

Pimobendan (Pimobendan) has myocardial Ca as a novel mechanism of action which is not present in conventional anti-heart failure drugs ²⁺ The sensitivity enhancing effect belongs to a new classification of anti-heart failure drugs, namely "Calciumsensitizer". In addition, the medicine has the effect of inhibiting the activity of Phospholipid (PDE) III. Based on these, the drug is an oral heart failure remedy exhibiting a positive sexual function and a vasodilating action with good energy efficiency.

A compound medicine composition containing benazepril and pimobendan is a veterinary medicine for treating dog congestive heart failure. Congestive heart failure is a condition in which the heart is unable to pump enough blood around the body. This can lead to exercise intolerance (inability to perform physical activity), breathing difficulties and fluid sensations.

Disclosure of Invention

The purpose of the invention is: overcomes the defects in the prior art, and provides the compound pharmaceutical composition containing benazepril and pimobendan for pets, which has convenient administration, lasting effect and stable curative effect.

In order to solve the technical problems, the technical scheme adopted by the invention is as follows:

a compound pharmaceutical composition containing benazepril and pimobendan for pets comprises the following raw material medicines in percentage by weight: 1 to 8.0 percent of benazepril hydrochloride, 0.5 to 4.0 percent of pimobendan, 42 to 71 percent of diluent, 1 to 5 percent of slow-release framework, 10 to 20 percent of coating taste masking material, 1.5 to 4 percent of disintegrating agent, 1 to 5 percent of adhesive, 5 to 15 percent of solubilizer, 1 to 5 percent of flow aid, 1 to 3 percent of lubricant, 0.5 to 2 percent of flavoring agent and less than or equal to 1 percent of pigment.

Furthermore, the compound pharmaceutical composition is a double-layer tablet, and the benazepril hydrochloride and the pimobendan are respectively positioned on different color tablet layers, namely a benazepril hydrochloride tablet layer and a pimobendan tablet layer.

Further, the solubilizer is one or more selected from succinic acid, stearic acid, fumaric acid, citric acid, sodium dodecyl sulfate and tween 80.

Further, the coating and taste masking material is Eudragit E100;

the diluent is one or more of microcrystalline cellulose, lactose, starch, pregelatinized starch and calcium hydrogen phosphate;

the disintegrating agent is one or more selected from crospovidone, low-substituted hydroxypropyl cellulose, sodium carboxymethyl starch, and croscarmellose sodium;

the adhesive is one or more of polyvidone, high-substituted hydroxypropyl cellulose and hydroxypropyl methylcellulose;

the glidant is selected from one of silicon dioxide and colloidal silicon dioxide;

the lubricant is one or more of magnesium stearate, calcium stearate, glyceryl behenate and pulvis Talci.

Further, the flavoring agent is selected from one of beef flavor, chicken flavor and composite meat flavor.

Another object of the invention is: the preparation method not only maintains all active ingredients of the raw material medicines, but also ensures that the two ingredients are dissolved and released in the same time, and can release the medicine stably and safely on the basis of achieving the optimal combined drug effect.

a preparation method of a compound pharmaceutical composition containing benazepril and pimobendan for pets comprises the following steps:

a preparation process of white lamellar particles, a preparation process of brown lamellar particles and a tabletting process;

the preparation process of the white lamellar particles comprises the following steps:

1) Preparation process of sustained-release particles:

weighing raw materials of povidone, purified water, benazepril hydrochloride, microcrystalline cellulose, hydroxypropyl methylcellulose, eiteqi E100, ethanol and purified water according to a proportion;

uniformly mixing povidone and purified water, and preparing povidone aqueous solution as a binder solution; mixing benazepril hydrochloride, microcrystalline cellulose and hydroxypropyl methylcellulose uniformly, and granulating with binder solution to obtain sustained-release particles;

2) The preparation process of the taste masking layer coating comprises the following steps:

mixing Eiteqi E100 with ethanol and purified water, and making into water solution of Eiteqi ethanol for masking taste; adding the sustained-release particles into coating equipment, preheating for 10-20 min to the material temperature of 30-40 ℃, and then carrying out taste-masking coating;

3) And (3) drying: after the taste masking and coating are finished, drying in coating equipment, and controlling the water content of the granules to be less than or equal to 4 percent;

4) Sieving: sieving the taste-masked coated granules with a 30-mesh sieve for finishing;

5) Mixing: adding additional auxiliary materials, and uniformly mixing to obtain white lamellar total mixed particles;

the preparation process of the brown lamellar particles comprises the following steps:

1) Process for producing solid Dispersion

Weighing succinic acid, pimobendan, polyvidone, ethanol, purified water, microcrystalline cellulose and crospovidone according to a certain proportion;

heating and melting succinic acid, adding pimobendan, uniformly mixing, and preparing a solid dispersion on spray drying equipment;

2) Process for producing pellets

Uniformly mixing povidone, ethanol and purified water, adding a proper amount of pigment, and preparing a brown povidone ethanol aqueous solution as a binder solution; uniformly mixing the solid dispersion, microcrystalline cellulose and crospovidone, and granulating by using an adhesive solution to obtain wet granules;

3) And (3) drying: after wet granules are prepared, drying the granules in coating equipment, and controlling the water content of the granules to be less than or equal to 4 percent;

4) Sieving: sieving the dried granules with a 30-mesh sieve for size stabilization;

5) Mixing: adding additional auxiliary materials, and uniformly mixing to obtain total mixed particles of the brown lamellar;

the tabletting process comprises the following steps: tabletting by adopting a double-color tablet tabletting machine.

Furthermore, the weight of the white slice is 100-120 mg, and the weight of the brown slice is 200-240 mg.

Further, the difference of the weight of the benazepril hydrochloride layer and the pimobendan hydrochloride layer is controlled within +/-5%.

The technical scheme adopted by the invention has the beneficial effects that:

the compound composition prepared by the invention has the characteristics of convenient administration, lasting effect and stable curative effect, can relax blood vessels and reduce blood pressure so as to relieve cardiac burden, and can increase myocardial contractility and improve the survival rate of sick dogs; the medicine has fast effect and high bioavailability; and because of adding the taste-masking coating process and a proper amount of meat flavor corrective, the pet-friendly taste is provided, so that the animal compliance is greatly improved.

The invention contains two active substances, namely pimobendan and benazepril hydrochloride, is suitable for dogs which use pimobendan and benazepril hydrochloride with the same dosage as single medicaments to control heart failure, can relax blood vessels and reduce blood pressure so as to relieve cardiac burden (the higher the peripheral pressure is, the stronger the force required by cardiac ejection), and can increase myocardial contractility and prolong the life of dogs with heart failure.

By adopting the process means of the compound pharmaceutical composition, the easily soluble benazepril hydrochloride is respectively prepared into a slow release skeleton, the difficultly soluble pimobendan is prepared into a solid dispersion, then the two prepared mixtures are added into a rotary bicolor tablet press to prepare white and brown double-layer tablets, and the two active ingredients are respectively arranged in different color tablet layers, so that all active ingredients of the raw materials are maintained; and because benazepril is a quick-release component, the dissolution is slowed down by a slow-release process, pimobendan is an insoluble component, and the dissolution is accelerated by a solid dispersion process, namely, the dissolution is regulated to be synchronous by slowing down one component, so that the two components are dissolved and released in the same time, and the stable drug release and the safe drug use can be realized on the basis of achieving the optimal combined drug effect.

The composition is prepared into white and brown double-layer tablets, and has the advantages of attractive appearance, capability of distinguishing production and clear knowledge that the composition is a compound preparation after the composition is prepared into the tablets.

Drawings

Fig. 1 is a flow chart of a preparation method of the compound pharmaceutical composition of the invention.

FIG. 2 is a graph of the in vitro dissolution profile of the tablet of example 1 of the present invention.

FIG. 3 is a graph of the in vitro dissolution profile of the tablet of example 1 of the present invention.

FIG. 4 is a graph of the in vitro dissolution profile of the tablet of example 1 of the present invention.

Detailed Description

The invention will now be described in further detail with reference to specific embodiments and the accompanying drawings. The following examples are intended to provide those skilled in the art with a more complete understanding of the present invention, and are not intended to limit the scope of the present invention. Reference herein to "one embodiment" or "an embodiment" means that a particular feature, structure, or characteristic may be included in at least one implementation of the invention. The appearances of the phrase "in one embodiment" in various places in the specification are not necessarily all referring to the same embodiment, nor are separate or alternative embodiments mutually exclusive of other embodiments.

Example 1

A compound double-layer tablet containing benazepril and pimobendan for pets comprises the following raw materials in percentage by weight: 1.0% of benazepril hydrochloride, 0.5% of pimobendan, 70.5% of diluent, 3% of sustained-release framework, 10% of coating taste masking material, 3% of disintegrant, 2% of adhesive, 5% of solubilizer, 1% of glidant, 2% of lubricant, 1% of flavoring agent and 1% of pigment.

In this example, the prescription of benazepril hydrochloride pimobendan tablets for pets is as follows:

in the prescription, the sustained-release framework is hydroxypropyl methylcellulose.

The solubilizer is selected from succinic acid.

The coating and taste masking material is Eudragit E100.

The diluent is microcrystalline cellulose.

The disintegrant is crospovidone.

The adhesive is polyvidone.

The flavoring agent is beef flavor.

The glidant is silicon dioxide.

The lubricant is magnesium stearate.

Referring to fig. 1, the preparation method of benazepril hydrochloride pimobendan tablets for pets comprises the following steps:

the raw materials are weighed and then prepared according to the following steps.

(1) Process for producing white lamellar particles

1.1 preparation Process of sustained-Release particles

Uniformly mixing povidone and purified water, and preparing povidone aqueous solution as a binder solution, wherein the mass ratio of the povidone to the purified water is 1 (10-12); the benazepril hydrochloride, the microcrystalline cellulose and the hydroxypropyl methylcellulose are uniformly mixed and granulated by using an adhesive solution to obtain the sustained-release particles. Povidone, also known as polyvinylpyrrolidone (PVP), is a non-ionic polymer compound that is soluble in cold water to form a solution with a certain viscosity, and is one of the most widely used binders.

1.2 preparation of taste-masking layer coating

Selecting Eiteqi E100 to be evenly mixed with ethanol and purified water, preparing a taste-masking water solution of the Eiteqi ethanol, and preparing the ethanol and the purified water into 80 percent of ethanol water, wherein the percent by volume of the Eiteqi E100 to the ethanol water is 100 percent of the volume of the Eiteqi E100 to the ethanol water, and the mass ratio of the Eiteqi E100 to the ethanol water is 1 (13-15); adding the sustained-release particles into coating equipment, preheating for 10-20 min to the material temperature of 30-40 ℃, and then carrying out taste-masking coating. Such as: and (3) performing taste masking coating on the sustained-release particles by adopting a fluidized bed side spraying mode. The chemical composition of the yuteqi E100 is a copolymer of butyl methacrylate, dimethylaminoethyl methacrylate and methyl methacrylate (1.

1.3, drying: after the taste-masking coating is finished, drying in coating equipment, and controlling the water content of the granules to be less than or equal to 4%.

1.4 sieving: sieving the taste-masked coated granules with a 30-mesh sieve for size stabilization.

1.5 mixing: adding additional auxiliary materials, and uniformly mixing to obtain the white lamellar total mixed particles.

(2) Preparation procedure of brown lamellar particles

2.1 preparation procedure of solid Dispersion: selecting succinic acid, heating and melting, adding pimobendan, mixing uniformly, and preparing a solid dispersion on spray drying equipment.

2.2 preparation procedure of granules

Selecting polyvidone, ethanol and purified water, mixing, and making into 20% v/v-80% ethanol water, wherein the mass ratio of polyvidone to ethanol water is 1 (12-13), adding appropriate amount of pigment, and making into brown polyvidone ethanol water solution as binder solution; and (3) uniformly mixing the solid dispersion, microcrystalline cellulose and crospovidone, and granulating by using a binder solution to obtain wet granules.

2.3, drying: after wet granules are prepared, the granules are dried in coating equipment, and the water content of the granules is controlled to be less than or equal to 4 percent.

2.4 sieving: sieving the dried granules with a 30-mesh sieve for size stabilization.

2.5, mixing: adding additional auxiliary materials, and uniformly mixing to obtain the total mixed particles of the brown sheet layers.

(3) Tabletting: tabletting by using a double-color tablet tabletting machine, wherein the weight of the white tablet is about 110mg, the weight of the brown tablet is about 220mg, and the total tablet weight is about 330mg; the tablet weight difference is controlled within +/-5%. The invention can only control the slice weight of the white part within 100-120 mg and the slice weight of the brown part within 200-240 mg.

(4) A packaging procedure: the setting temperature is adjusted according to the difference between the room temperature and the aluminum plastic packaging material, and the sealing is proper.

Example 2

The pharmaceutical composition of example 2 was prepared in the same manner as in example 1.

Example 3

The pharmaceutical composition of example 3 was prepared according to the same method as example 1.

And (3) related performance detection:

the benazepril pimobendan hydrochloride tablets for pets prepared in examples 1-3 are subjected to detection of correlation performance by adopting a conventional detection method in the field, and the detection results are as follows:

1. in vitro dissolution test

Absorption of a drug after oral administration of a solid formulation depends on dissolution or release of the drug from the formulation, dissolution of the drug under physiological conditions, and permeation in the gastrointestinal tract. Since dissolution and dissolution of a drug have a significant impact on absorption, in vitro dissolution tests have the potential to predict its behavior in vivo.

Taking 12 tablets of the tested preparation, carrying out dissolution test under appropriate and mild test conditions, such as 75 rpm by a paddle method, and carrying out dissolution control by adopting a multipoint detection method to obtain a dissolution curve of the medicine. Dissolution data are as follows:

the dissolution profile was plotted against in vitro dissolution data, see in particular figure 2.

The dissolution profile was plotted against in vitro dissolution data, see in particular figure 3.

From the in vitro dissolution data, the compound bilayer tablets prepared in examples 1-3 successfully control the dissolution release of the soluble benazepril hydrochloride and the insoluble pimobendan within the same time, and can achieve stable drug release and safe drug administration on the basis of achieving the optimal combined drug effect.

2. Pet palatability study

The clinically collected dogs were subjected to an acceptance survey of benazepril pimobendan hydrochloride tablets for pets prepared in the above examples 1 to 3, and the test results were as follows:

example 1

Example 2

Example 3

Note: active ingestion means: the benazepril hydrochloride pimobendan tablets for the pets are placed in an empty feed bowl and are eaten by clinical dogs within 1 minute.

Acceptance means: the benazepril hydrochloride pimobendan tablets for the pets are put into the mouths of clinical dogs and are eaten by the clinical dogs within 1 minute.

The term repellency means: in both of the above experiments, the clinical dog was not judged to be acceptable if it did not receive the benazepril hydrochloride pimobendan tablets for pets.

And (4) conclusion: the benazepril pimobendan hydrochloride tablets prepared in examples 1-3 can be well accepted by dogs and have good palatability.

3. Pharmacodynamic study

To demonstrate the efficacy of the present invention in the treatment of Congestive Heart Failure (CHF) in dogs, a 3-panel, blinded, randomized clinical study was conducted. The study included 3 administration groups, which were pimobendan hydrochloride tablets (n = 32), pimobendan tablet + benazepril hydrochloride tablet administration group i (n = 17), pimobendan tablet + benazepril hydrochloride tablet administration group ii (n = 12).

Dogs recruited congestive heart failure with myxoid mitral disease in this trial were asked to meet the following criteria:

1) Characteristic murmurs associated with mitral insufficiency;

2) Chest X-ray shows cardiac enlargement;

3) There was radiographic evidence of clinical signs and pulmonary edema consistent with congestive heart failure.

4) The body weight is more than or equal to 2.5 kg

The administration dose of the pimobendan and benazepril hydrochloride tablet is 0.25 to 0.5mg/kg of pimobendan and 0.125 to 0.25mg/kg of benazepril hydrochloride, and the administration dose is 2 times per day. The administration dosage of the pimobendan tablet and the benazepril hydrochloride tablet administration group I is 0.125 to 0.5mg/kg of pimobendan, 0.17 to 0.35mg/kg of benazepril hydrochloride, and the administration is carried out for 2 times per day. The administration dosage of the pimobendan tablet and the benazepril hydrochloride tablet in the group II is 0.25 to 1mg/kg of pimobendan for 1 time every day, and 0.17 to 0.35mg/kg of benazepril hydrochloride for 2 times every day. The administration was continued for 56 days. The use of other positive inotropic drugs or angiotensin II receptor antagonists was banned during the study.

Dogs were examined at D7 + -1, D14 + -2, D28 + -2 and D56 + -3 and any early withdrawal. Including physical examination, and recording body weight, rectal temperature, body Condition Score (BCS) and CHF signs. The efficacy is judged mainly by the total clinical score (GCS), and is the unweighted sum of scores of a numerical score scale determined aiming at exercise tolerance (1 to 4 min), stopping (1 to 4 min), appetite (1 to 4 min), breathing difficulty (1 to 4 min), cough (1 to 4 min) and breathing difficulty at night (1 to 4 min). GCS ranges from 6 to 23, with lower scores indicating less severe CHF symptoms.

The experimental result shows that the overall clinical score of all administration groups is obviously reduced compared with 0 day; there were no significant differences in overall clinical scores between groups. There were no significant differences between groups in the frequency of the relevant clinical chemistry and hematological variables or all adverse events. The pimobendan and benazepril hydrochloride tablet administration group (11.2%) had a significantly lower vomiting frequency than the control group I + II (43.6%) (p = 0.0071).

It can be concluded that the drug effect of pimobendan hydrochloride benazepril tablets was non-inferior to the two control groups and that significantly less vomiting was observed compared to the two control groups.

In light of the foregoing description of the preferred embodiment of the present invention, many modifications and variations will be apparent to those skilled in the art without departing from the spirit and scope of the invention. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention. The technical scope of the present invention is not limited to the content of the specification, and must be determined according to the scope of the claims.

Claims

1. A compound pharmaceutical composition containing benazepril and pimobendan for pets is characterized in that: the pharmaceutical composition comprises the following raw material medicines in percentage by weight: 1 to 8.0 percent of benazepril hydrochloride, 0.5 to 4.0 percent of pimobendan, 42 to 71 percent of diluent, 1 to 5 percent of slow release framework, 10 to 20 percent of coating taste masking material, 1.5 to 4 percent of disintegrant, 1 to 5 percent of adhesive, 5 to 15 percent of solubilizer, 1 to 5 percent of glidant, 1 to 3 percent of lubricant, 0.5 to 2 percent of flavoring agent and pigment less than or equal to 1 percent; the compound pharmaceutical composition is a double-layer tablet, and the benazepril hydrochloride and the pimobendan are respectively positioned on different color layers, namely a benazepril hydrochloride layer and a pimobendan layer;

the preparation method of the compound pharmaceutical composition containing benazepril and pimobendan for pets is characterized by comprising the following steps: the preparation method comprises the following steps:

1) Preparation process of sustained-release particles: weighing raw materials of povidone, purified water, benazepril hydrochloride, microcrystalline cellulose, hydroxypropyl methylcellulose, eiteqi E100 and ethanol according to a proportion;

mixing Ewing E100, ethanol and purified water, and making into water solution of Ewing ethanol for masking taste; adding the sustained-release particles into coating equipment, preheating for 10-20 min to the material temperature of 30-40 ℃, and then carrying out taste-masking coating;

3) And (3) drying: after the taste-masking layer is coated, drying in coating equipment, and controlling the water content of the granules to be less than or equal to 4 percent;

1) Process for producing solid Dispersion

Weighing succinic acid, pimobendan, polyvidone, ethanol, purified water, microcrystalline cellulose, and polyvinylpolypyrrolidone according to a certain proportion; heating and melting succinic acid, adding pimobendan, uniformly mixing, and preparing a solid dispersion on spray drying equipment;

2) Process for producing pellets

4) Sieving: sieving the dried granules with a 30-mesh sieve for finishing;

the tabletting process comprises the following steps: tabletting by adopting a double-color tablet tabletting machine;

the weight of the white slice part is 100-120 mg, and the weight of the brown slice part is 200-240 mg;

the additional auxiliary materials are a glidant, a lubricant and a flavoring agent,

the glidant is selected from one of silicon dioxide and colloidal silicon dioxide; the lubricant is one or more of magnesium stearate, calcium stearate, glyceryl behenate and talcum powder;

the flavoring agent is one of beef flavor, chicken flavor and composite meat flavor.

2. The compound pharmaceutical composition containing benazepril and pimobendan for pets according to claim 1, which is characterized in that: the difference of the weight of the benazepril hydrochloride lamella and the pimobendan hydrochloride lamella is controlled within +/-5%.