CN103446073A - (S)-carvedilol capsule preparation and preparation method for same - Google Patents
(S)-carvedilol capsule preparation and preparation method for same Download PDFInfo
- Publication number
- CN103446073A CN103446073A CN2013103126327A CN201310312632A CN103446073A CN 103446073 A CN103446073 A CN 103446073A CN 2013103126327 A CN2013103126327 A CN 2013103126327A CN 201310312632 A CN201310312632 A CN 201310312632A CN 103446073 A CN103446073 A CN 103446073A
- Authority
- CN
- China
- Prior art keywords
- carvedilol
- parts
- preparation
- capsule preparations
- diluent
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a (S)-carvedilol capsule preparation. The (S)-carvedilol capsule preparation is composed of the raw materials in the parts by weight: 50-150 parts of (S)-carvedilol, 5-10 parts of a diluent, 2-10 parts of a lubricant, 2-10 parts of a disintegrant, and 5-15 parts of a tackifier. The invention further provides a preparation method for the preparation. The preparation disclosed by the invention is remarkable in curative effect on hypertension, far lower than commercially available carvedilol in toxicity, capable of being normally taken in dosage range, high in safety, high in bioavailability, and convenient to absorb. The preparation disclosed by the invention is easy to prepare and convenient for large-scale production.
Description
Technical field
The present invention relates to a kind of medicament capsule preparation and preparation method thereof, specifically a kind of (S)-carvedilol capsule preparations and preparation method thereof.
Background technology
There are 600,000,000 hyperpietics in the whole world.If can not obtain timely, effectively treatment, this common disorder of hypertension just may increase the risk that heart failure, apoplexy and renal failure occur.Congestive heart failure (congestive heart failure, CHF) is the heart damage caused by the cardiovascular diseases, and its prevalence is ascendant trend gradually, is one of modal reason of being critically ill and dying suddenly.Studies confirm that at present, beta-blocker can effectively be intervened generation, the development of congestive heart failure by multiple mechanism of action.
Carvedilol is the medicine that represents of third generation adrenergic receptor blocker, has very strong beta-receptor retardation, has blocking-up α concurrently
1-receptor and vasodilatory pharmacological mechanism, have calcium antagonism during high concentration, renin angiotensin aldosterone system capable of blocking.Domestic clinical research in nearly 2 years proves, carvedilol can significantly reduce the M & M of heart failure, can also prevent apoptotic generation, and this is also the key factor that this medicine produces clinical beneficial effect, is that traditional beta-blocker can not be compared simultaneously.Therefore, carvedilol for idiopathic light, moderate hypertension and anginal treatment, is also the unique indication of current China approval for clinical treatment at first.Its antihypertensive effect is good, and side effect is less, has possessed characteristics safe, gentle blood pressure lowering.Clinical research is also found; this medical instrument has the multiple effect of neuro hormone antagonism; can protect strongly vascular endothelial cell; the migration and the propagation that suppress vascular smooth muscle cell; can reduce peripheral vascular resistance and delay apoptosis simultaneously; minimizing, with myocardial infarction and the heart failure risk of cardiac insufficiency, is the choice drug that hypertension complicated has angina pectoris or Patients With Myocardial Infarction.
Carvedilol is for having nonselective beta-receptor retardance, alpha 1-receptor retardation.Clinical use be its racemic modification (its (S)-carvedilol with (R)-carvedilol ratio be 1:1).According to Nichols AJ(1989) report, the receptor blocking agent active function of (S)-carvedilol is 100 times of (R)-carvedilol, both alpha-receptor blockeres are quite active.According to international relevant report (Stoschitzky K, 2001), current research finds that only (S)-carvedilol has the beta-receptor blocking effect at present, and (R)-carvedilol has the effect of the sympathetic activity of enhancing, by alpha-receptor, blocks and reduces blood pressure.This explanation (S)-carvedilol and (R)-carvedilol have different pharmacological actions.
About carvedilol, there are many patents to relate at present, as Chinese patent CN102740838A discloses a kind of being used for the treatment of and/or the angiocardiopathy preventing controlled release form.This controlled release agent comprises the carvedilol for the treatment of effective dose or its medical acceptable salt, substrate forms polymer, solubility enhancer and excipient.This substrate form polymer comprise following one or more: the how elegant K15M of U.S. of 20-60 % by weight, the how elegant K100M of U.S. of 15-20 % by weight, the how elegant E4M of U.S. of 25-35 % by weight, especially very RSPO or the 35-55 % by weight WSRN12NF of 35-45 % by weight.
It is 1 part of carvedilol and 1～10 part of carrier that Chinese patent CN1931141A discloses its parts by weight of a kind of carvedilol dripping pill.Preparation method is that carvedilol is added in the carriers such as Polyethylene Glycol of melting and forms uniform dispersion, and the dispersion of melting is splashed in coolant refined plant oil or dimethicone and forms drop pill.Dropping pill formulation of the present invention is compared with other preparation, solved in carvedilol water do not dissolve, drug effect is slow and bioavailability is low shortcoming, preparation technology of the present invention is suitable for suitability for industrialized production simultaneously.
Chinese patent CN101380312A discloses a kind of enteric coated preparation of carvedilol, by percentage by weight, is that 1～10% carvedilol, 5～20% enteric materials, 70～94% pharmaceutic adjuvants are made; The clinical effectiveness of the existing oral tablet of carvedilol enteric preparation of the present invention and capsule obviously improves, it has effectively avoided the carvedilol stimulation that disintegrate produces gastric mucosa rapidly under one's belt, can make medicine stop the long period at enteral, thereby extend its drug effect.
Chinese patent CN102525977A discloses a kind of compositions of the carvedilol for direct compression, this carvedilol compositions is prepared from by carvedilol, adjuvant, surfactant, lubricant and fluidizer, the weight portion proportion relation of each raw material is as follows: 5～10 parts of carvedilols, 30～60 parts of adjuvants, 0～5 part, surfactant, 0～5 part of lubricant, 0～5 part of fluidizer.Carvedilol for direct compression compositions of the present invention adopts direct compression process to prepare tablet, absorbs soon, and rapid-action, bioavailability is high; Reduce processing step, saved man-hour, reduced production cost, improved production efficiency.
Carvedilol is as a kind of medicine of comparative maturity, and type of dosage form is abundanter.But still there are some untoward reaction in carvedilol, as: severe hypotension, bradycardia, cardiac insufficiency, cardiogenic shock and cardiac arrest may be caused, also respiratory problems, tracheospasm, vomiting, unconsciousness and tic may be occurred.
Studies confirm that (S)-carvedilol has under low concentration well reduces blood pressure, improves significantly cardiac function and protect myocardium effect; can significantly reduce apoptosis of cardiac muscle; reduce I, III Collagen Type VI precipitation; and can significantly reduce the expression of CHF rat AQP2mRNA, thereby suppress left ventricular remodeling.Acute toxicity test in mice also shows that (S)-carvedilol compares with racemic modification, has the higher characteristics of safety.(S)-carvedilol is compared with its racemic modification and is had stronger activity and higher safety.As chiral drug, the technology content of (S)-carvedilol is higher, with racemic modification, compares, and it has stronger activity and higher safety, and for further improving clinical efficacy, reducing toxic and side effects provides assurance.
Summary of the invention
Goal of the invention: the object of the present invention is to provide a kind of (S)-carvedilol capsule preparations, safe to realizing, activity is high, bioavailability is high, untoward reaction is few, more be applicable to clinical practice.The present invention also provides the preparation method of said preparation.
Technical scheme: in order to realize the foregoing invention purpose, the technical solution adopted in the present invention is:
A kind of (S)-carvedilol capsule preparations, be comprised of the raw material of following parts by weight: (S)-50～150 parts of carvedilols, 5～10 parts of diluent, 2～10 parts of lubricants, 2～10 parts of disintegrating agents, 5～15 parts of tackifiers.
Further, said preparation is comprised of the raw material of following parts by weight: (S)-70～120 parts of carvedilols, 5～8 parts of diluent, 5～10 parts of lubricants, 5～10 parts of disintegrating agents, 5～10 parts of tackifiers.
Described diluent is one or more in mannitol, microcrystalline Cellulose, lactose.
Described lubricant is one or more in magnesium stearate, glyceryl monostearate, Pulvis Talci.
Described disintegrating agent is one or more in cross-linking sodium carboxymethyl cellulose, corn starch, polyvinylpolypyrrolidone.
Described tackifier is the fine micro-element of hydroxypropyl methyl.
The method of preparation (S)-carvedilol capsule preparations is: (the S)-carvedilol, diluent and the disintegrating agent that take recipe quantity, supplementary material is crossed to 60～80 mesh sieves standby, after mix homogeneously, the tackifier aqueous solution that adds mass concentration 2%, be mixed and made into soft material, granulate through 24～30 mesh sieves.60～80 ℃ of oven dry, 20～25 mesh sieve granulate, add the lubricant of recipe quantity to mix, filled capsules and get final product.
Described diluent is mannitol, microcrystalline Cellulose or lactose; Described disintegrating agent is cross-linking sodium carboxymethyl cellulose, corn starch or polyvinylpolypyrrolidone; Described tackifier is the fine micro-element of hydroxypropyl methyl; Described lubricant is magnesium stearate, glyceryl monostearate or Pulvis Talci.
Preferably, adopt equivalent incremental method mix homogeneously after described supplementary material sieving for standby.
Beneficial effect: compared with prior art, remarkable advantage of the present invention is: preparation of the present invention is evident in efficacy on treatment hypertension; Preparation toxicity of the present invention is far smaller than commercially available carvedilol, and can normally take in dosage range, and safety is higher; Preparation bioavailability of the present invention is high, is convenient to absorb.Preparation of the present invention is easy to preparation, is convenient to large-scale production.
The specific embodiment
Below by specific embodiment, the present invention is further described; it should be pointed out that for the person of ordinary skill of the art, under the premise without departing from the principles of the invention; can also make some modification and improvement, these also should be considered as belonging to protection scope of the present invention.
Embodiment 1
With (S)-carvedilol 50g, mannitol 5g, magnesium stearate 2g, cross-linking sodium carboxymethyl cellulose 2g, the fine micro-plain 5g of hydroxypropyl methyl.Make 1000 (S)-carvedilol capsules.Preparation process is: take (S)-carvedilol, mannitol and cross-linking sodium carboxymethyl cellulose, supplementary material is crossed to 60 mesh sieves standby, after mix homogeneously, add the fine micro-plain aqueous solution of hydroxypropyl methyl of mass concentration 2%, be mixed and made into soft material, granulate through 24 mesh sieves.60 ℃ of oven dry, 20 mesh sieve granulate, add magnesium stearate to mix, filled capsules and get final product.
Embodiment 2
With (S)-carvedilol 150g, microcrystalline Cellulose 10g, glyceryl monostearate 10g, corn starch 10g, the fine micro-plain 15g of hydroxypropyl methyl.Make 1000 (S)-carvedilol capsules.Preparation process is: take (S)-carvedilol, microcrystalline Cellulose and corn starch, supplementary material is crossed to 80 mesh sieves standby, after mix homogeneously, add the fine micro-plain aqueous solution of hydroxypropyl methyl of mass concentration 2%, be mixed and made into soft material, granulate through 30 mesh sieves.80 ℃ of oven dry, 25 mesh sieve granulate, add glyceryl monostearate to mix, filled capsules and get final product.
Embodiment 3
With (S)-carvedilol 100g, lactose 8g, Pulvis Talci 8g, polyvinylpolypyrrolidone 8g, the fine micro-plain 10g of hydroxypropyl methyl.Make 1000 (S)-carvedilol capsules.Preparation process is: take (S)-carvedilol, lactose and polyvinylpolypyrrolidone, supplementary material is crossed to 70 mesh sieves standby, after mix homogeneously, add the fine micro-element of hydroxypropyl methyl of mass concentration 2%, be mixed and made into soft material, granulate through 26 mesh sieves.70 ℃ of oven dry, 25 mesh sieve granulate, add Pulvis Talci to mix, filled capsules and get final product.
Embodiment 4
The present embodiment further proves the therapeutic effect of preparation of the present invention by clinical trial.
According to conditions of patients, select 100 hyperpietics to carry out the system clinical observation, test group, each 50 examples of matched group.Test group is taken medicine described in embodiment 2, usage and dosage: oral, be grown up one time 1,2 times on the one, in early morning and sleep before take; Matched group is taken commercially available Carvedilol Tablets, usage and dosage: oral, be grown up one time 1,2 times on the one, in early morning and sleep before take; Observing 3 months, one month is a course for the treatment of, totally 3 courses for the treatment of.
Efficacy assessment standard:
Produce effects: after taking a course for the treatment of, blood pressure recovers normal level, follows up a case by regular visits to 3 months blood pressure stabilizations without the recidivist;
Effectively: take after a course for the treatment of hypertension symptom and alleviate but still, higher than the normal arterial pressure scope, continue to take one or two course for the treatment of,
Blood pressure recovers normal level;
Invalid: after taking a course for the treatment of, hypertension symptom, without improving or adding severe one, continues to take still without improving.
The curative effect of test group and matched group clinical trial is as shown in the table:
| Group | Case load | Produce effects | Effectively | Invalid | Total effective rate % |
| Test group | 50 | 41 | 9 | 0 | 100% |
| Matched group | 50 | 15 | 23 | 12 | 76% |
Test data in upper table is added up and is shown, take the patient of this medicine, what significant curative effect was arranged accounts for 82%, and matched group significant curative effect arranged account for 30%, hence one can see that, test group has the matched group that is far longer than of significant curative effect, and the total effective rate test group, far away higher than matched group, has the value of clinical expansion.
Embodiment 5
The present embodiment carries out toxicology test to the S-carvedilol.
One, experimental animal
Kunming mouse, body weight 13-15g, supplied with by Nanjing University of Technology's Experimental Animal Center.
Two, experiment condition
Before and after administration, the experiment mice male and female are divided cage, with full-valence pellet feed, feed, freely drink water, and room temperature: 24～26 ℃, humidity: 50～64%.
Three, experimental technique and result
(1) acute toxicity test
Mice is divided into to test group and matched group, every group of male and female half and half, test group is pressed the dosage of 0.5mL/20g body weight to the mouse stomach administration to mice with the S-carvedilol; Matched group is to pressing the dosage of 0.5mL/20g body weight to the mouse stomach administration with carvedilol to mice.After administration, Continuous Observation is 14 days, at least observes every day 1 time.During off-test, survival mice is through dissecting, and naked eyes have no the obvious ANOMALOUS VARIATIONS of each main organs.
Test data is in Table 1.Visible, no matter the S-carvedilol is oral or intravenous injection, LD
50all, far away higher than carvedilol, illustrate that the toxicity of S-carvedilol is less than carvedilol.
Table 1
(2) long term toxicity test
To S-carvedilol gastric infusion for mice, according to basic, normal, high dosed administration, be respectively 30.0,100.0,300.0mg/(kg.d) when (in body surface area, be 12,24,96 times of the pharmacodynamics effective dose, be about with dosage 6,16,48 times of clinical plan), after successive administration 4 weeks and after drug withdrawal observes 2 weeks (convalescent period), have no animal dead, no abnormal in low and middle dosage group, observe apertor oculi in high dose group loose, the eye semi-closure, luminous reflectance is blunt etc.Animal blood is conventional, blood biochemistry checking except high dose group AST value higher than matched group, all the other indices are all substantially within normal range, animal system is dissected the perusal no abnormality seen, Main Organ Coefficients is substantially in range of normal value, microscopy as a result low dose group without obvious Pathological, middle and high dosage group shows the property a crossed hemoglobin, erythrocytopenia, the focus of visible bronchia pneumonia sometimes.
Claims (9)
1. (S)-carvedilol capsule preparations, it is characterized in that being comprised of the raw material of following parts by weight: (S)-50～150 parts of carvedilols, 5～10 parts of diluent, 2～10 parts of lubricants, 2～10 parts of disintegrating agents, 5～15 parts of tackifiers.
2. (S)-carvedilol capsule preparations as claimed in claim 1, it is characterized in that being formed by the raw material of following parts by weight: (S)-70～120 parts of carvedilols, 5～8 parts of diluent, 5～10 parts of lubricants, 5～10 parts of disintegrating agents, 5～10 parts of tackifiers.
3. (S)-carvedilol capsule preparations as claimed in claim 1, it is characterized in that: described diluent is one or more in mannitol, microcrystalline Cellulose, lactose.
4. (S)-carvedilol capsule preparations claimed in claim 1, it is characterized in that: described lubricant is one or more in magnesium stearate, glyceryl monostearate, Pulvis Talci.
5. (S)-carvedilol capsule preparations claimed in claim 1, it is characterized in that: described disintegrating agent is one or more in cross-linking sodium carboxymethyl cellulose, corn starch, polyvinylpolypyrrolidone.
6. (S)-carvedilol capsule preparations claimed in claim 1 is characterized in that: described tackifier is the fine micro-element of hydroxypropyl methyl.
7. the method for preparing (S)-carvedilol capsule preparations as claimed in claim 1, it is characterized in that: the step of described method is: (the S)-carvedilol, diluent and the disintegrating agent that take recipe quantity, supplementary material is crossed to 60～80 mesh sieves standby, after mix homogeneously, the tackifier aqueous solution that adds mass concentration 2%, be mixed and made into soft material, granulate through 24～30 mesh sieves.60～80 ℃ of oven dry, 20～25 mesh sieve granulate, add the lubricant of recipe quantity to mix, filled capsules and get final product.
8. the method for preparation as claimed in claim 7 (S)-carvedilol capsule preparations, it is characterized in that: described diluent is mannitol, microcrystalline Cellulose or lactose; Described disintegrating agent is cross-linking sodium carboxymethyl cellulose, corn starch or polyvinylpolypyrrolidone; Described tackifier is the fine micro-element of hydroxypropyl methyl; Described lubricant is magnesium stearate, glyceryl monostearate or Pulvis Talci.
9. the method for preparation as claimed in claim 7 (S)-carvedilol capsule preparations, is characterized in that: adopt equivalent incremental method mix homogeneously after described supplementary material sieving for standby.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2013103126327A CN103446073A (en) | 2013-07-24 | 2013-07-24 | (S)-carvedilol capsule preparation and preparation method for same |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2013103126327A CN103446073A (en) | 2013-07-24 | 2013-07-24 | (S)-carvedilol capsule preparation and preparation method for same |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN103446073A true CN103446073A (en) | 2013-12-18 |
Family
ID=49729195
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2013103126327A Pending CN103446073A (en) | 2013-07-24 | 2013-07-24 | (S)-carvedilol capsule preparation and preparation method for same |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103446073A (en) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101380312A (en) * | 2008-10-13 | 2009-03-11 | 青岛黄海制药有限责任公司 | Carvedilol enteric preparation and preparation method thereof |
| CN102285910A (en) * | 2011-07-04 | 2011-12-21 | 南京工业大学 | Method for preparing (S)-carvedilol |
-
2013
- 2013-07-24 CN CN2013103126327A patent/CN103446073A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101380312A (en) * | 2008-10-13 | 2009-03-11 | 青岛黄海制药有限责任公司 | Carvedilol enteric preparation and preparation method thereof |
| CN102285910A (en) * | 2011-07-04 | 2011-12-21 | 南京工业大学 | Method for preparing (S)-carvedilol |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN101632678B (en) | Losartan potassium hydrochlorothiazide composition and preparation method thereof | |
| CN101406472A (en) | Pharmaceutical composition of atenolol/amlodipine/folacin compound and uses thereof | |
| CN101926793B (en) | Combined medicament containing telmisartan and aliskiren and preparation method thereof | |
| CN102008708A (en) | Ramipril-contained compound preparation for treating hypertension | |
| CN102342944A (en) | Medicament composition for treating hypertension | |
| CN101653440B (en) | Treatment composition containing amlodipine series salt and pril medicament | |
| CN101134032A (en) | Compound preparations for treating hypertension and method for preparing the same | |
| CN103446073A (en) | (S)-carvedilol capsule preparation and preparation method for same | |
| CN103860511B (en) | A kind of Pharmaceutical composition containing Irbesartan and Amlodipine Besylate Tablet and preparation method thereof | |
| CN101849942B (en) | Medicinal composition for treating hypertension | |
| CN101214379A (en) | Novel composing prescription sustained-release preparation for treating high blood pressure and preparation method thereof | |
| CN1270711C (en) | Aminochlorodipin, irbesartan compound preparation | |
| CN103721259A (en) | Angiotensin II receptor blocker/thiazide diuretics/5-methyltetrahydrofolate pharmaceutical composition | |
| CN103656609A (en) | Trandolapril dispersion pharmaceutical composition | |
| CN102125528A (en) | Domperidone orally disintegrating tablet | |
| CN101254181B (en) | Hypertension-treating medicine combination | |
| CN101890024A (en) | Candesartan cilexetil/hydrochlorothiazide composition and preparation method thereof | |
| CN101422459A (en) | Atenolol/nitrendipine/folic-acid compound medicine combination and use thereof | |
| CN103142618A (en) | Metroprolol succinate hydrochlorothiazide sustained-release pellet capsule and preparation method thereof | |
| CN101254182B (en) | Hypertension-treating medicine combination | |
| CN108125914A (en) | A kind of olmesartan medoxomil hydrochlorothiazide Compound preparation | |
| CN102579442B (en) | Compound preparation containing benidipine hydrochloride and atorvastatin calcium and application for compound preparation | |
| CN100423779C (en) | Medicinal composition comprising active components of 5-HT 3 receptor antagonist and H2 receptor antagonist and use thereof | |
| CN102552873A (en) | Levoamlodipine, aliskiren and pril compound antihypertensive medicine | |
| CN102430109A (en) | Amlodipine, aliskiren and pril compound antihypertensive medicament |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C12 | Rejection of a patent application after its publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20131218 |