CN112043677A - Clonidine hydrochloride sustained-release micro-tablets and preparation method and application thereof - Google Patents
Clonidine hydrochloride sustained-release micro-tablets and preparation method and application thereof Download PDFInfo
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4168—1,3-Diazoles having a nitrogen attached in position 2, e.g. clonidine
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
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- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
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- A61P27/06—Antiglaucoma agents or miotics
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Abstract
The invention relates to the technical field of sustained-release medicines, in particular to a clonidine hydrochloride sustained-release micro-tablet and a preparation method and application thereof. The clonidine hydrochloride sustained-release micro-tablet comprises the following components in percentage by weight: clonidine hydrochloride: 3-6%, gel skeleton: 68-86%, lubricant: 0.5-2%, filler: 10-25%, the preparation method comprises the steps of irradiating all raw materials with gamma-rays for sterilization before use, and the following operations are carried out in an aseptic environment: mixing all the raw materials uniformly in a mortar, grinding, and pressing into small pieces with diameter of 3mm by direct tabletting method and maximum pressure of opposite sex tabletting machine. Compared with clonidine hydrochloride eye drops, the clonidine hydrochloride sustained-release micro-tablet for eyes has good controlled-release effect, can prolong the detention time of a medicament in eyes, reduce the times of administration, improve the compliance of patients, improve the bioavailability of the medicament, and can reduce the toxic and side effects of a central nervous system; the preparation process is simple and has good practical application value.
Description
Technical Field
The invention relates to the technical field of sustained-release medicines, in particular to a clonidine hydrochloride sustained-release micro-tablet and a preparation method and application thereof.
Background
The information in this background section is only for enhancement of understanding of the general background of the invention and is not necessarily to be construed as an admission or any form of suggestion that this information forms the prior art that is already known to a person of ordinary skill in the art.
Clonidine hydrochloride, which is chemically named 2- [ (2, 6-dichloroaniline) -2 imino ] -imidazolidine hydrochloride, is an alpha-adrenoceptor agonist, is currently used as a second-line drug for hypertension, is a clonidine hydrochloride sustained-release tablet developed by the 2009 FDA-approved Addrenex Pharmaceuticals company, is used for treating hypertension, is approved by the FDA in the united states in 2010 for increasing indications, and is used for treating Attention Deficit Hyperactivity Disorder (ADHD) of children and adolescents. In addition, in the treatment of glaucoma, clonidine hydrochloride inhibits its activity by agonizing peripheral sympathetic alpha 2-receptors in negative feedback, reduces aqueous humor formation, lowers intraocular pressure, and has no influence on pupil size, photoreaction, and regulatory function. But its long-term use is limited by its effect on the central nervous system and the resulting significant systemic arterial pressure drop.
In the treatment of glaucoma, eye drops are most commonly used for topical administration to the eye, but the amount of penetration into conjunctival vessels is limited because of rapid clearance due to blinking, tear drainage, and the like, and about 75% of the dose is almost immediately drained through the nasolacrimal duct when eye drops are administered, and it is necessary to increase the frequency of administration or increase the dose of administration in order to maintain the therapeutic drug concentration level. Some high molecular viscosity increasing agents such as methylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone and polyvinyl alcohol are added into eye drops, so that it is expected to prolong the residence time of the drug in the eye and improve the bioavailability of the drug, but the release rate of the drug is not easily controlled, resulting in rapid outflow of the drug from the polymer.
In the prior art, clonidine hydrochloride dosage forms comprise oral quick-release tablets, sustained-release tablets, dripping pills, injection, transdermal patches and the like, but the inventor finds that the existing clonidine hydrochloride dosage forms have not ideal therapeutic effect on eye diseases.
Disclosure of Invention
Compared with the clonidine hydrochloride eye drops, the ophthalmic clonidine hydrochloride sustained-release micro-tablet has good controlled-release effect, can prolong the detention time of the drug in the eyes, reduce the administration times, improve the compliance of patients, improve the bioavailability of the drug, and reduce the toxic and side effects of the central nervous system, and has simple preparation process and good practical application value.
Specifically, the technical scheme of the invention is as follows:
in a first aspect of the present invention, a clonidine hydrochloride sustained release micro-tablet is provided, which comprises the following components by weight:
clonidine hydrochloride: 3 to 6 percent
Gel skeleton: 68 to 86 percent
Lubricant: 0.5 to 2 percent
Filling agent: 10 to 25 percent.
Preferably, the gel skeleton is selected from one or more of hypromellose, carbomer and ethyl cellulose, and is further preferably selected from hypromellose and carbomer;
further preferably, the weight ratio of the hydroxypropyl methylcellulose to the carbomer is as follows: 65-80: 3 to 6.
Preferably, the lubricant is selected from sodium stearyl fumarate, magnesium stearate or talc; further preferred is sodium stearyl fumarate.
Preferably, the filler is selected from mannitol or microcrystalline cellulose, and more preferably mannitol.
Further, the hypromellose is preferably HPMC RG 4T.
Further, the carbomer is preferably carbomer 974P.
In a second aspect of the present invention, there is provided a method for preparing the clonidine hydrochloride sustained release micro-tablet of the first aspect, wherein clonidine hydrochloride and adjuvants hypromellose, carbomer, sodium stearyl fumarate and mannitol are sterilized by γ -ray irradiation before use, and the following operations are all performed in a sterile environment: mixing clonidine hydrochloride and adjuvants with mortar, grinding, and tabletting with anisotropic tabletting machine under maximum pressure to obtain tablet with diameter of 3 mm.
In a third aspect of the present invention, there is provided a use of the clonidine hydrochloride sustained release mini-tablets of the first aspect as an ophthalmic preparation.
The specific embodiment of the invention has the following beneficial effects:
compared with clonidine hydrochloride eye drops, the clonidine hydrochloride sustained-release micro-tablet for eyes in the embodiment of the invention has good controlled-release effect, can prolong the detention time of the drug in the eyes, reduce the times of medication, improve the compliance of patients, improve the bioavailability of the drug and reduce the toxic and side effects of the central nervous system;
the method has simple preparation process and good practical application value.
Drawings
The accompanying drawings, which are incorporated in and constitute a part of this specification, are included to provide a further understanding of the invention, and are incorporated in and constitute a part of this specification, illustrate exemplary embodiments of the invention and together with the description serve to explain the invention and not to limit the invention.
Fig. 1 is an in vitro release profile of clonidine hydrochloride sustained release mini-tablets prepared in example 1.
Fig. 2 is an in vitro release profile of clonidine hydrochloride sustained release mini-tablets prepared in example 2.
Fig. 3 is an in vitro release profile of clonidine hydrochloride sustained release mini-tablets prepared in example 3.
Fig. 4 is an in vitro release profile of clonidine hydrochloride sustained-release mini-tablets prepared in comparative example 1.
Fig. 5 is an in vitro release profile of clonidine hydrochloride sustained-release mini-tablets prepared in comparative example 2.
Detailed Description
The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out according to conventional conditions or according to conditions recommended by the manufacturers.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. The reagents or starting materials used in the present invention can be purchased from conventional sources, and unless otherwise specified, the reagents or starting materials used in the present invention can be used in a conventional manner in the art or in accordance with the product specifications. In addition, any methods and materials similar or equivalent to those described herein can be used in the methods of the present invention. The preferred embodiments and materials described herein are intended to be exemplary only.
As discussed in the background section, eye drops are most commonly used in topical ocular administration in the prior art, but have low bioavailability due to rapid clearance caused by blinking, tear drainage, and increased frequency or dosage to maintain therapeutic drug concentration levels. The prior clonidine hydrochloride dosage form has not ideal therapeutic effect on eye diseases.
In view of the above, the invention provides an ophthalmic clonidine hydrochloride sustained release micro-tablet, and a preparation method and application thereof.
In one embodiment of the present invention, a clonidine hydrochloride sustained release micro tablet is provided, which comprises the following components by weight:
clonidine hydrochloride: 3 to 6 percent
Gel skeleton: 68 to 86 percent
Lubricant: 0.5 to 2 percent
Filling agent: 10 to 25 percent.
In a specific embodiment, the gel skeleton is selected from one or more of hypromellose, carbomer and ethylcellulose, and is further preferably selected from hypromellose and carbomer; furthermore, the weight ratio of the hydroxypropyl methylcellulose to the carbomer is as follows: 65-80: 3 to 6.
The hydroxypropyl methylcellulose and the carbomer are used as hydrophilic gel frameworks and are matched with each other to play a role in slowly releasing the medicine, and through experimental research of the inventor, the slow release effect is best when the hydroxypropyl methylcellulose and the carbomer used in the embodiment of the invention are used as the hydrophilic gel frameworks together.
In a particular embodiment, the lubricant is selected from sodium stearyl fumarate, magnesium stearate, or talc; further preferred is sodium stearyl fumarate; the lubricant sodium stearyl fumarate can promote the dissolution of the medicine, and is non-toxic and non-irritant.
In a particular embodiment, the filler is selected from mannitol or microcrystalline cellulose, further preferably mannitol; the mannitol is added, so that the mannitol is quickly dissolved in the gel to generate a pore channel, the dissolution of the medicine is improved, and the release of the medicine is facilitated.
In a more specific embodiment, the hypromellose is preferably HPMC RG 4T;
in a more specific embodiment, the carbomer is preferably carbomer 974P type.
In one embodiment of the present invention, there is provided a method for preparing the above clonidine hydrochloride sustained release mini-tablets, wherein all the raw materials, i.e., clonidine hydrochloride and the auxiliary materials are sterilized by γ -ray irradiation before use, and the following operations are performed in an aseptic environment: mixing clonidine hydrochloride and adjuvants with mortar, grinding, and tabletting with anisotropic tabletting machine under maximum pressure to obtain tablet with diameter of 3 mm.
In one embodiment of the invention, the application of the clonidine hydrochloride sustained-release micro-tablets as an ophthalmic preparation is provided.
The clonidine hydrochloride sustained-release micro-tablets are used for eyes, prolong the detention time of the clonidine hydrochloride in the eyes, can reduce the administration times, increase the bioavailability, maintain the slow release of the medicine and reduce the side effect of long-term overdose administration on the central nervous system.
The invention is further illustrated by the following examples, which are not to be construed as limiting the invention thereto. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention.
Example 1
The clonidine hydrochloride sustained-release micro-tablet prescription is as follows:
clonidine hydrochloride: 5 percent of
Hydroxypropyl methylcellulose RG 4T: 75 percent of
Carbomer 974P: 4 percent of
Sodium stearyl fumarate: 1 percent of
Mannitol: 15 percent of
The above raw materials were sterilized by gamma irradiation before use, and the following operations were carried out in a sterile environment. The raw materials were mixed well in a mortar, ground and compressed into small pieces having a diameter of 3mm by a direct compression method using a foreign tabletting machine ((Korsch-EKO model, Berlin, Germany) with maximum pressure.
Example 2
The clonidine hydrochloride sustained-release micro-tablet prescription is as follows:
clonidine hydrochloride: 5 percent of
Hydroxypropyl methylcellulose RG 4T: 65 percent of
Carbomer 974P: 10 percent of
Sodium stearyl fumarate: 1 percent of
Mannitol: 17 percent.
The preparation method is the same as example 1.
Example 3
The clonidine hydrochloride sustained-release micro-tablet prescription is as follows:
clonidine hydrochloride: 5 percent of
Hydroxypropyl methylcellulose RG 4T: 80 percent of
Carbomer 974P: 3 percent of
Sodium stearyl fumarate: 1 percent of
Mannitol: 14 percent.
The preparation method is the same as example 1.
Comparative example 1
The clonidine hydrochloride sustained-release micro-tablet prescription is as follows:
clonidine hydrochloride: 5 percent of
Hydroxypropyl methylcellulose RG 4T: 79 percent
Sodium stearyl fumarate: 1 percent of
Mannitol: 15 percent.
The preparation method is the same as example 1.
Comparative example 2
The ophthalmic clonidine hydrochloride micro-tablet prescription is as follows:
clonidine hydrochloride: 5 percent of
Hydroxypropyl methylcellulose RG 4T: 60 percent of
Carbomer 974P: 19 percent of
Sodium stearyl fumarate: 1 percent of
Mannitol: 15 percent.
The preparation method is the same as example 1.
Examples of the experiments
The clonidine hydrochloride sustained-release micro-tablets obtained in examples and comparative examples were measured for tablet weight difference, hardness and friability, water absorption, and in vitro release properties.
1. Taking 20 micro-tablets, precisely weighing the total weight, and obtaining the average tablet weight and Standard Deviation (SD) value, wherein the results are shown in Table 1;
2. taking 10 micro tablets, and testing by using a tablet hardness tester (YD-2), wherein the results are shown in Table 1;
3. water absorption: the water absorption of the micro-tablets is related to the release of the drug from the micro-tablets. Taking 3 micro-tablets, precisely weighing the micro-tablets, and respectively placing the micro-tablets in a pre-weighing device (W)0) In a settling basket of (1), paddle method, 900mL of water, 37 ℃, stirring at 50rpm, taking out until the weight does not increase any more, blotting excess water, and weighing (W)i) The water absorption is calculated according to the following formula:
water absorption rate of (W)i-W0)/W0X 100%, the results are given in Table 1.
4. Precisely weighing the mass of the microchip, transferring the microplate into a glass bottle containing 1mL of isotonic phosphate buffer solution with pH 7.4, covering a rubber stopper to prevent liquid evaporation, placing the glass bottle in an oscillator under the oscillation condition of 25rpm, 32 +/-1 ℃, sampling 300 mu L at 20min, 40min, 60min, 90min, 120min, 180min, 240min, 300min, 420min and 1440min, and immediately supplementing the isotonic phosphate buffer solution with the equal volume of pH 7.4 after sampling. The absorbance was measured according to the general rules of the four departments of the "Chinese pharmacopoeia" version of ultraviolet-visible spectrophotometry, and the cumulative release was calculated according to the standard curve, and the results are shown in FIGS. 1 to 4. The release curve of fig. 1 shows that the clonidine hydrochloride sustained-release mini-tablets prepared in example 1 can be released for 7 hours continuously, and the cumulative release amount of 7 hours can reach 85.4 +/-0.87%; the release curve of fig. 2 shows that the clonidine hydrochloride sustained-release mini-tablets prepared in example 2 can be released for 7 hours continuously, and the cumulative release amount of 7 hours can reach 87.4 +/-0.80%; FIG. 3 shows the release curve that the clonidine hydrochloride sustained release mini-tablets prepared in example 3 can be released for 7 hours continuously, and the cumulative release amount of 7 hours can reach 86.7 +/-0.51%; FIG. 4 shows the release curve that the clonidine hydrochloride sustained-release mini-tablets prepared in comparative example 1 can be released for 7h continuously, and the cumulative release amount of 7h can reach 67.7 +/-2.25%; the release curve of fig. 5 shows that the clonidine hydrochloride sustained-release mini-tablets prepared in comparative example 2 can be released for 7 hours continuously, and the cumulative release amount of 7 hours can reach 65.1 +/-0.25%.
TABLE 1 tablet weight, hardness, water absorption results for clonidine hydrochloride sustained release mini-tablets
From the experimental data, the clonidine hydrochloride sustained-release micro-tablets prepared by the embodiment of the invention have good sustained-release effect, can be continuously released for 7 hours, and have the highest accumulative release amount reaching 87.4 +/-0.80%; the highest 7h accumulative release amount of the clonidine hydrochloride sustained-release micro-tablets prepared by the comparative example reaches 67.7 +/-2.25%. Compared with the prior art, the clonidine hydrochloride sustained-release micro-tablets with better sustained-release effect can be obtained by selecting the composition components and the dosage.
The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention, and various modifications and changes may be made by those skilled in the art. 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.
Claims (10)
1. The clonidine hydrochloride sustained-release micro-tablet is characterized by comprising the following components in percentage by weight:
clonidine hydrochloride: 3 to 6 percent
Gel skeleton: 68 to 86 percent
Lubricant: 0.5 to 2 percent
Filling agent: 10 to 25 percent.
2. The clonidine hydrochloride sustained-release micro-tablet of claim 1, wherein the gel matrix is selected from one or more of hypromellose, carbomer, and ethylcellulose.
3. The clonidine hydrochloride sustained-release mini-tablet of claim 2, wherein the gel matrix is hypromellose and carbomer.
4. The clonidine hydrochloride sustained-release micro-tablet of claim 3, wherein the gel matrix is hypromellose and carbomer in a weight ratio of: 65-80: 3 to 6.
5. The clonidine hydrochloride sustained-release mini-tablets of claim 1, wherein the lubricant is selected from sodium stearyl fumarate, magnesium stearate or talc; sodium stearyl fumarate is preferred.
6. The clonidine hydrochloride sustained-release mini-tablet according to claim 1, wherein the filler is selected from mannitol or microcrystalline cellulose, preferably mannitol.
7. The clonidine hydrochloride sustained-release mini-tablet of claim 2, wherein the hypromellose is hypromellose RG 4T.
8. The clonidine hydrochloride sustained release mini-tablet of claim 2, wherein the carbomer is carbomer model 974P.
9. A method for preparing clonidine hydrochloride sustained release micro-tablets according to claim 1, comprising the steps of: clonidine hydrochloride and adjuvants hypromellose, carbomer, sodium stearyl fumarate, mannitol are sterilized by gamma-ray irradiation before use, and the following operations are all performed in a sterile environment: mixing clonidine hydrochloride and adjuvants with mortar, grinding, and tabletting with anisotropic tabletting machine under maximum pressure to obtain tablet with diameter of 3 mm.
10. Use of clonidine hydrochloride sustained release mini-tablets according to claim 1 as ophthalmic preparation.
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2020
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Application publication date: 20201208 |