CN103705480A - Guanfacine hydrochloride sustained-release preparation and preparation method thereof - Google Patents
Guanfacine hydrochloride sustained-release preparation and preparation method thereof Download PDFInfo
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- CN103705480A CN103705480A CN201310744328.XA CN201310744328A CN103705480A CN 103705480 A CN103705480 A CN 103705480A CN 201310744328 A CN201310744328 A CN 201310744328A CN 103705480 A CN103705480 A CN 103705480A
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Abstract
The invention discloses a guanfacine hydrochloride sustained-release preparation and a preparation method thereof. The guanfacine hydrochloride sustained-release preparation is prepared from guanfacine hydrochloride, filler, a medicine carrier material, a pH regulator, a lubricating agent and a disintegrating agent. The preparation method comprises the steps of crushing and sieving the guanfacine hydrochloride, the filler, the pH regulator and the medicine carrier material respectively, uniformly mixing the guanfacine hydrochloride with the filler, the pH regulator and the medicine carrier material in a mixing machine, then sequentially adding the lubricating agent and the disintegrating agent into the mixing machine and mixing uniformly, and finally, tabletting with a conventional method to prepare the guanfacine hydrochloride sustained-release tablets with various specifications. Due to the utilization of the method for preparing the guanfacine hydrochloride sustained-release preparation, the operation process can be effectively simplified, impurities in the finished preparation are reduced and the medicine safety is improved; besides, the prepared guanfacine hydrochloride sustained-release preparation has good stability and dissolution characteristic.
Description
Technical field
The present invention relates to pharmaceutical field about drug preparation technique, be specifically related to a kind of guanidine hydrochloride sustained release and preparation method thereof.
Background technology
U.S. FDA has been ratified Guanfacine Hydrochloride slow releasing tablet and has been used for the treatment of 6～17 years old child and teenager attention-deficient and hyperkinetic syndrome.It is first selectivity α 2a-adrenergic receptor agonist of getting permission in the world so far to treat this indication.Guanfacine Hydrochloride chemical name is N-amidino groups-2-(2,6-Dichlorobenzene base) acetamide mono-hydrochloric salts, its molecular formula is: C
9h
9cl
2n
3oHCl, molecular weight is 282.55, structural formula is:
Guanfacine Hydrochloride be white to off-white color crystalline powder, be insoluble in water and ethanol, in methanol, have relatively high dissolubility (>30mg/mg).
Preclinical study is found, the receptors bind of Guanfacine Hydrochloride energy directly and in prefrontal cortex, and the excitement of postsynaptic α 2a-receptor just may produce enhancing working memory, reduces the degree of diverting one's attention, improve attention adjusting, raising Behavior inhibition power and strengthen to get excited and control texts.
Within 2009, SHIRE company has obtained the approval of guanidine hydrochloride sustained release first at FDA; because slow release formulation can effectively reduce Cmax; prolong drug action time; can be used for new indication-attention deficit hyperactivity disorder (Attention-deficit hyperactivity disorder; ADHD) treatment; evident in efficacy; the child that those are suffered to ADHD and behavior disorder is simultaneously particularly useful, and has relevant United States Patent (USP) to protect the Therapeutic Method of this Guanfacine Hydrochloride slow release medication.Guanfacine Hydrochloride dissolubility in the solution of different pH is obviously different, has significant pH dependency, and in acid, dissolubility is better, and along with the rising of pH, dissolubility significantly reduces.Therefore, between the resulting slow releasing preparation of common preparation method, usually there are the following problems: the pharmacokinetic parameters such as differences between batches are large, release poor stability, the interior bioavailability of body are undesirable.
Summary of the invention
The technical problem to be solved in the present invention is to provide a kind of guanidine hydrochloride sustained release and preparation method thereof.Utilize technical solution of the present invention to prepare guanidine hydrochloride sustained release, can effectively simplify the operation course, the impurity reducing in finished product preparation produces, and improves the safety of medicine.Utilize guanidine hydrochloride sustained release prepared by technical solution of the present invention to there is good stability and dissolution characteristic.
In order to address the above problem, the technical solution used in the present invention is:
The invention provides a kind of guanidine hydrochloride sustained release, the free guanfacine effective content 1mg specification in every slow releasing preparation of take is benchmark, described every guanidine hydrochloride sustained release is by Guanfacine Hydrochloride 1.14mg, filler 40～57mg, drug carrier material 66.2～86.2mg, pH adjusting agent 17～24mg, lubricant 3.4～5.4mg and disintegrating agent 4.26～6.8 mg make;
Described filler is pregelatinized Starch or sorbitol; Described drug carrier material is hydroxyethylmethyl-cellulose, hydroxyethyl-cellulose, Carboxymethyl cellulose sodium and at least one in strange 100 especially; Described pH adjusting agent is tartaric acid, citric acid, malic acid or fumaric acid; Described lubricant is Macrogol 4000, polyethylene glycol 6000, PEG 8000 or magnesium laurylsulfate; Described disintegrating agent is crospolyvinylpyrrolidone or cross-linking sodium carboxymethyl cellulose.
A preparation method for guanidine hydrochloride sustained release, described preparation method comprises the following steps:
A, according to the supplementary material proportioning of above-mentioned guanidine hydrochloride sustained release, prepare various supplementary materials, first principal agent Guanfacine Hydrochloride was pulverized to 100 mesh sieves, filler, pH adjusting agent and drug carrier material were pulverized to 80 mesh sieves;
B, principal agent Guanfacine Hydrochloride is put into mixer with filler, pH adjusting agent and drug carrier material mix, mix homogeneously;
C, then successively lubricant and disintegrating agent are joined in mixer and mixed respectively, after mixing, obtain uniform mixed powder; Finally, according to conventional method tabletting, make the Guanfacine Hydrochloride sustained release tablet products of all size.
According to the preparation method of above-mentioned guanidine hydrochloride sustained release, the sheet of described Guanfacine Hydrochloride slow releasing tablet is heavily 150 or 300mg; In products obtained therefrom Guanfacine Hydrochloride slow releasing tablet, the effective dose of free guanfacine is 1mg or 2mg.
positive beneficial effect of the present invention:
1, utilize technical solution of the present invention to prepare guanidine hydrochloride sustained release, can effectively simplify the operation course, the impurity reducing in finished product preparation produces, and improves the safety of medicine.
2, technical solution of the present invention has good repeatability, is applicable to industrialized great production, owing to simplifying the operation course, can effectively reduce production energy resource consumption, reduces production costs.
3, utilize the guanidine hydrochloride sustained release that technical solution of the present invention is produced to there is good stability and dissolution characteristic.Adopt existing Guanfacine Hydrochloride slow releasing tablet as reference preparation, the drug release determination condition of the Guanfacine Hydrochloride sheet of including with reference to American Pharmacopeia, pass through drug release determination, the dissolution in vitro of proved invention product Guanfacine Hydrochloride slow releasing tablet is consistent with reference preparation, effectively guarantees safety and the effectiveness of medicine.
Below data further illustrate beneficial effect of the present invention by experiment:
Utilize the 1mg Guanfacine Hydrochloride slow releasing tablet that the embodiment of the present invention 1 is made to test, according to drug release determination method (appendix X D first method), adopt dissolution method (appendix X D the second method) device, pass through external standard method, proved invention guanidine hydrochloride sustained release has good stability, compares and has remarkable result with existing product and prior art.
Above-mentioned about release experiment condition of the present invention: dissolution the second subtraction unit, rotating speed is 50rpm, and temperature is 37 ℃, and release medium is 500ml, the hydrochloride buffer of pH1.0, detection method is high performance liquid chromatography.
accompanying drawing explanation:
The vitro release figure of three batches of different samples of Fig. 1 embodiment of the present invention 1 gained under pH1.0 condition;
The vitro release figure of three batches of different samples of Fig. 2 embodiment of the present invention 1 gained under pH4.5 condition;
The vitro release figure of three batches of different samples of Fig. 3 embodiment of the present invention 1 gained under pH6.8 condition;
Three batches of different samples of Fig. 4 embodiment of the present invention 1 gained in water vitro release figure.
the specific embodiment:
Below in conjunction with embodiment, further set forth the present invention, but do not limit content of the present invention.
Embodiment 1:
The free guanfacine effective content 1mg specification in every slow releasing preparation of take is benchmark, and the raw material of every Guanfacine Hydrochloride slow releasing tablet consists of: Guanfacine Hydrochloride 1.14mg, pregelatinized Starch 41.6mg, Carboxymethyl cellulose sodium 46mg, hydroxyethyl-cellulose 36mg, citric acid 17mg, magnesium laurylsulfate 4mg and cross-linking sodium carboxymethyl cellulose 4.26mg.
The present embodiment is benchmark according to free guanfacine effective content 1mg specification in above-mentioned every slow releasing preparation, and the raw material of producing 5000 Guanfacine Hydrochloride slow releasing tablet consists of: Guanfacine Hydrochloride 5.7g, pregelatinized Starch 208g, Carboxymethyl cellulose sodium 230g, hydroxyethyl-cellulose 180g, citric acid 85g, magnesium laurylsulfate 20g and cross-linking sodium carboxymethyl cellulose 21.3g.
In addition, according to the raw material of 5000 Guanfacine Hydrochloride slow releasing tablet, form 2500 of the Guanfacine Hydrochloride slow releasing tablet that can be prepared into free guanfacine effective content 2mg.
Embodiment 2:
The free guanfacine effective content 1mg specification in every slow releasing preparation of take is benchmark, and the raw material of every Guanfacine Hydrochloride slow releasing tablet consists of: Guanfacine Hydrochloride 1.14mg, pregelatinized Starch 40mg, Carboxymethyl cellulose sodium 49.4mg, hydroxyethyl-cellulose 30mg, tartaric acid 20.6mg, Macrogol 4000 4.4mg and crospolyvinylpyrrolidone 4.26mg.
The present embodiment is benchmark according to free guanfacine effective content 1mg specification in above-mentioned every slow releasing preparation, and the raw material of producing 5000 Guanfacine Hydrochloride slow releasing tablet consists of: Guanfacine Hydrochloride 5.7g, pregelatinized Starch 200g, Carboxymethyl cellulose sodium 247g, hydroxyethyl-cellulose 150g, tartaric acid 103g, Macrogol 4000 22g and crospolyvinylpyrrolidone 21.3g.
In addition, according to the raw material of 5000 Guanfacine Hydrochloride slow releasing tablet, form 2500 of the Guanfacine Hydrochloride slow releasing tablet that can be prepared into free guanfacine effective content 2mg.
Embodiment 3:
The free guanfacine effective content 1mg specification in every slow releasing preparation of take is benchmark, and the raw material of every Guanfacine Hydrochloride slow releasing tablet consists of: Guanfacine Hydrochloride 1.14mg, pregelatinized Starch 57mg, especially strange 100 80.8mg, malic acid 22.86mg, Macrogol 4000 5.4mg and cross-linking sodium carboxymethyl cellulose 6mg.
The present embodiment is benchmark according to free guanfacine effective content 1mg specification in above-mentioned every slow releasing preparation, and the raw material of producing 5000 Guanfacine Hydrochloride slow releasing tablet consists of: Guanfacine Hydrochloride 5.7g, pregelatinized Starch 285g, especially strange 100 404g, malic acid 114.3g, Macrogol 4000 27g and cross-linking sodium carboxymethyl cellulose 30g.
In addition, according to the raw material of 5000 Guanfacine Hydrochloride slow releasing tablet, form 2500 of the Guanfacine Hydrochloride slow releasing tablet that can be prepared into free guanfacine effective content 2mg.
Embodiment 4:
The free guanfacine effective content 1mg specification in every slow releasing preparation of take is benchmark, and the raw material of every Guanfacine Hydrochloride slow releasing tablet consists of: Guanfacine Hydrochloride 1.14mg, sorbitol 48.26mg, hydroxyethylmethyl-cellulose 40mg, hydroxyethyl-cellulose 26.2mg, tartaric acid 24mg, Macrogol 4000 4mg and cross-linking sodium carboxymethyl cellulose 6.4mg.
The present embodiment is benchmark according to free guanfacine effective content 1mg specification in above-mentioned every slow releasing preparation, and the raw material of producing 5000 Guanfacine Hydrochloride slow releasing tablet consists of: Guanfacine Hydrochloride 5.7g, sorbitol 241.3g, hydroxyethylmethyl-cellulose 200g, hydroxyethyl-cellulose 131g, tartaric acid 120g, Macrogol 4000 20g and cross-linking sodium carboxymethyl cellulose 32g.
In addition, according to the raw material of 5000 Guanfacine Hydrochloride slow releasing tablet, form 2500 of the Guanfacine Hydrochloride slow releasing tablet that can be prepared into free guanfacine effective content 2mg.
Embodiment 5:
The free guanfacine effective content 1mg specification in every slow releasing preparation of take is benchmark, and the raw material of every Guanfacine Hydrochloride slow releasing tablet consists of: Guanfacine Hydrochloride 1.14mg, sorbitol 46.06mg, especially strange 100 76.2mg, malic acid 17mg, magnesium laurylsulfate 4mg and crospolyvinylpyrrolidone 5.6mg.
The present embodiment is benchmark according to free guanfacine effective content 1mg specification in above-mentioned every slow releasing preparation, and the raw material of producing 5000 Guanfacine Hydrochloride slow releasing tablet consists of: Guanfacine Hydrochloride 5.7g, sorbitol 230.3g, especially strange 100 381g, malic acid 85g, magnesium laurylsulfate 20g and crospolyvinylpyrrolidone 28g.
In addition, according to the raw material of 5000 Guanfacine Hydrochloride slow releasing tablet, form 2500 of the Guanfacine Hydrochloride slow releasing tablet that can be prepared into free guanfacine effective content 2mg.
Embodiment 6:
The free guanfacine effective content 1mg specification in every slow releasing preparation of take is benchmark, and the raw material of every Guanfacine Hydrochloride slow releasing tablet consists of: Guanfacine Hydrochloride 1.14mg, sorbitol 41.4mg, hydroxyethylmethyl-cellulose 46mg, hydroxyethyl-cellulose 29.4mg, citric acid 22mg, magnesium laurylsulfate 3.4mg and cross-linking sodium carboxymethyl cellulose 6.8mg.
The present embodiment is benchmark according to free guanfacine effective content 1mg specification in above-mentioned every slow releasing preparation, and the raw material of producing 5000 Guanfacine Hydrochloride slow releasing tablet consists of: Guanfacine Hydrochloride 5.7g, sorbitol 207g, hydroxyethylmethyl-cellulose 230g, hydroxyethyl-cellulose 147g, citric acid 110g, magnesium laurylsulfate 17g and cross-linking sodium carboxymethyl cellulose 34g.
In addition, according to the raw material of 5000 Guanfacine Hydrochloride slow releasing tablet, form 2500 of the Guanfacine Hydrochloride slow releasing tablet that can be prepared into free guanfacine effective content 2mg.
The preparation method of above-described embodiment 1～6 Guanfacine Hydrochloride slow releasing tablet of the present invention:
Supplementary material proportioning according to the arbitrary described Guanfacine Hydrochloride slow releasing tablet of above-described embodiment 1～6 is prepared various supplementary materials, first principal agent Guanfacine Hydrochloride is pulverized to 100 mesh sieves, and filler, pH adjusting agent and drug carrier material were pulverized to 80 mesh sieves; First principal agent Guanfacine Hydrochloride and filler, pH adjusting agent and drug carrier material are put into mixer mixing 30min, mix homogeneously; Successively lubricant and disintegrating agent are joined respectively in mixer and mix 30min again, after mixing, obtain uniform powder body; Finally, according to conventional method tabletting, making free guanfacine effective content is the Guanfacine Hydrochloride slow releasing tablet of 1mg or 2mg specification.
Claims (3)
1. a guanidine hydrochloride sustained release, it is characterized in that: the free guanfacine effective content 1mg specification in every slow releasing preparation of take is benchmark, described every guanidine hydrochloride sustained release is by Guanfacine Hydrochloride 1.14mg, filler 40～57mg, drug carrier material 66.2～86.2mg, pH adjusting agent 17～24mg, lubricant 3.4～5.4mg and disintegrating agent 4.26～6.8 mg make;
Described filler is pregelatinized Starch or sorbitol; Described drug carrier material is hydroxyethylmethyl-cellulose, hydroxyethyl-cellulose, Carboxymethyl cellulose sodium and at least one in strange 100 especially; Described pH adjusting agent is tartaric acid, citric acid, malic acid or fumaric acid; Described lubricant is Macrogol 4000, polyethylene glycol 6000, PEG 8000 or magnesium laurylsulfate; Described disintegrating agent is crospolyvinylpyrrolidone or cross-linking sodium carboxymethyl cellulose.
2. a preparation method for guanidine hydrochloride sustained release described in claim 1, is characterized in that, described preparation method comprises the following steps:
A, according to the supplementary material proportioning of guanidine hydrochloride sustained release described in claim 1, prepare various supplementary materials, first principal agent Guanfacine Hydrochloride was pulverized to 100 mesh sieves, filler, pH adjusting agent and drug carrier material were pulverized to 80 mesh sieves;
B, principal agent Guanfacine Hydrochloride is put into mixer with filler, pH adjusting agent and drug carrier material mix, mix homogeneously;
C, then successively lubricant and disintegrating agent are joined in mixer and mixed respectively, after mixing, obtain uniform mixed powder; Finally, according to conventional method tabletting, make the Guanfacine Hydrochloride sustained release tablet products of all size.
3. the preparation method of guanidine hydrochloride sustained release according to claim 2, is characterized in that: the sheet of described Guanfacine Hydrochloride slow releasing tablet is heavily 150 or 300mg; In products obtained therefrom Guanfacine Hydrochloride slow releasing tablet, the effective dose of free guanfacine is 1mg or 2mg.
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