CN108478535B - Theophylline slow-release dry suspension and preparation method thereof - Google Patents
Theophylline slow-release dry suspension and preparation method thereof Download PDFInfo
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Abstract
The theophylline slow-release dry suspension is prepared by a scientific method, and overcomes the defects that (1) the half-life period of a common theophylline oral preparation such as a theophylline tablet is short in treatment dosage range, high blood concentration can be generated, and toxic and side effects are high, and (2) other oral solid preparations such as a theophylline slow-release tablet, a slow-release granule and the like cause great inconvenience for sick old people and children, particularly patients who are difficult to swallow, although the defects of the common preparation are overcome. The invention has long half life, stable blood concentration, small toxic and side effect, is easy to be taken by old people and children patients, particularly patients who are difficult to swallow, is convenient to carry, and can be taken after a certain amount of the invention is stirred to be uniform suspension by a small amount of water.
Description
Technical Field
The invention belongs to the field of drug research and development, and particularly relates to a theophylline sustained-release dry suspension and a preparation method thereof
Background
Bronchial asthma is a common disease and frequently encountered disease, and the main symptoms are paroxysmal wheeze, shortness of breath, chest distress and cough. Bronchial asthma is a chronic inflammatory disease of the airways, which is involved by various cells (eosinophils, mast cells, T lymphocytes, neutrophils, airway epithelial cells and the like) and cell components, the chronic inflammation is related to airway hyperreactivity, and the chronic inflammation generally has wide and variable reversible airflow limitation, so that symptoms such as repeated wheezing, shortness of breath, chest distress and/or cough occur and are aggravated at night and/or in the early morning.
Theophylline (Theophylline) can reduce the tension of smooth muscle and expand respiratory tract, can promote the release of endogenous adrenaline and noradrenaline and relax airway smooth muscle, inhibit the release of calcium ions from smooth muscle endoplasmic reticulum and reduce the concentration of intracellular calcium ions to generate respiratory tract expansion effect, has stronger relaxation effect on the smooth muscle but is less than β receptor agonist, is mainly used for bronchial asthma, acute bronchitis, asthmatic bronchitis, obstructive emphysema and the like to relieve asthmatic symptoms, and is also suitable for the symptoms of chronic bronchitis and emphysema accompanied with bronchospasm.
However, because theophylline has large pharmacokinetic difference in different individuals, half-life period, narrow therapeutic dose range (plasma content of about 8-20mg/L), unstable blood concentration, higher blood concentration when being prepared into common dosage forms such as tablets, and certain toxic and side effects. In recent years, some countries have developed a plurality of preparations such as theophylline sustained-release tablets, theophylline sustained-release capsules and the like with long half-life, small toxic and side effects and long-acting oral therapy aiming at the problems of common theophylline preparations, but the preparations bring great inconvenience to patients for the elderly suffering from bronchial asthma and children, particularly patients who are difficult to swallow.
Disclosure of Invention
Sustained release formulation (SRP): the preparation has better treatment effect by delaying the drug release rate of the drug from the preparation and reducing the absorption rate of the drug entering the organism, and compared with other corresponding common preparations, the preparation has the advantages that the number of times of taking the drug per 24 hours is reduced from 3-4 times to 1-2 times.
The invention relates to a theophylline slow-release dry suspension and a preparation method thereof. The dry suspension prepared by the invention has the function of a long-acting preparation and solves the problem of difficult swallowing of patients.
The invention is completed according to the following technical scheme,
prescription:
150-250g of theophylline, 60-80g of cellulose, a proper amount of adhesive, 30-40g of surfactant, 20-30g of lactose, 20-30g of mannitol, 500-700g of sucrose and 0.1-1% of essence of 1-2% of hydroxypropyl methyl cellulose.
The preparation method comprises the following steps:
1. preparation of mother nucleus: placing cellulose in the formula into a centrifugal granulator, granulating with water as binder, drying at 40-60 deg.C, and collecting 40-60 mesh granules to obtain mother nucleus;
2. preparation of sustained-release granules: respectively crushing theophylline and a surfactant in a formula, passing the crushed theophylline and the surfactant through a 120-mesh screen with 100 meshes, uniformly mixing to prepare mixed powder, putting a mother nucleus in a centrifugal granulator, using a 2-3% hydroxypropyl cellulose aqueous solution as an adhesive, adjusting the rotating speed of a host machine to be 180-mesh and 200rpm/min, the air blowing flow to be 350-mesh and 450rpm, the air blowing pressure to be 0.5-0.6Map, the air blowing flow to be 15-20L/min, the rotating speed of a slurry pump to be 15-25rpm and the powder supply speed to be 10-20rpm, carrying out slurry supply and powder supply until the mixed powder is completely sprayed, continuing rotating the host machine for 5-8min, stopping the host machine, taking out the prepared particles, and carrying out air blowing drying at 40-60 ℃ to obtain;
3. preparing the theophylline sustained-release dry suspension: respectively pulverizing lactose, mannitol, sucrose and hydroxypropyl methylcellulose in the formula, sieving with 100 mesh sieve, mixing with the prepared sustained-release granules in a trough mixer for 20-25min, granulating with 18-20 mesh sieve using water as binder, drying at 40-60 deg.C, grading with 20 mesh sieve, spraying 0.1-1% essence, and mixing for 40-60min to obtain theophylline sustained-release dry suspension.
The binder can also be one or more of hydroxypropyl methylcellulose or hydroxypropyl cellulose or methylcellulose;
the surfactant is stearic acid and sodium dodecyl benzene sulfonate;
the adhesive is prepared into 2-3% aqueous solution by water;
1-2% of hydroxypropyl methyl cellulose refers to that the hydroxypropyl methyl cellulose accounts for 1-2% of the total prescription amount;
the slurry supply and the powder supply are carried out alternately after the slurry supply is carried out.
Advantageous effects
The theophylline slow-release dry suspension overcomes the defects that (1) a theophylline common oral preparation such as a theophylline tablet has a half-life period and a narrow therapeutic dose range, can generate higher blood concentration and has high toxic and side effects, and (2) other oral solid preparations such as a theophylline slow-release tablet, a slow-release granule and the like have great inconvenience for sick old people and children, particularly patients who are difficult to swallow, although the defects of the common preparation are overcome. The invention has long half life, stable blood concentration, small toxic and side effect, is easy to be taken by old people and children patients, particularly patients who are difficult to swallow, is convenient to carry, and can be taken after a certain amount of the invention is stirred to be uniform suspension by a small amount of water.
Description of the drawings: the FIGURE is a graph of the results of the release test of the present invention.
In the drawings: 1-release amount%; 2-absorbance%; 3-time (hours)
DETAILED DESCRIPTION OF EMBODIMENT (S) OF INVENTION
Example 1: theophylline slow release dry suspension agent release degree test
Precisely weighing 0.5g of theophylline dry suspension, according to a dissolution determination method, taking 900ml of water as a medium, carrying out sampling 2ml respectively at 37 +/-0.5 ℃ and a rotating basket rotating speed of 100r/min according to a law, after 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12 hours according to the law, simultaneously adding water with the same volume after sampling, filtering the sample by using a 0.45um microporous filter membrane, taking 1ml to 10ml of subsequent filtrate in a volumetric flask, adding water to a scale, measuring the absorbance at a wavelength of 270mm by using an ultraviolet spectrophotometry, and respectively calculating the release amount of the sample at different times, wherein the result is shown in the attached drawing:
as can be seen in the figure, the release amount reaches 60% within 1 hour, the drug is stably released within 1-11 hours, and the release amount is reduced after 11 hours, which proves that the sustained-release effect is achieved by the invention.
Example 2: preparation method 1 of theophylline sustained-release dry suspension
1. The preparation of the mother nucleus is carried out according to the preparation method in the invention;
2. preparation of sustained-release granules: respectively crushing theophylline and sodium dodecyl benzene sulfonate in a formula, sieving the crushed theophylline and sodium dodecyl benzene sulfonate with a 100-mesh sieve, uniformly mixing to prepare mixed powder, putting a mother nucleus in a centrifugal granulator, using a 2% hydroxypropyl cellulose aqueous solution as an adhesive, adjusting the rotating speed of a main engine to 200rpm/min, the air flow to 450rpm, the air injection pressure to 0.5Map, the air injection flow to 15L/min, the rotating speed of a guniting pump to 15rpm and the powder supply speed to 10rpm, carrying out slurry supply and powder supply until the mixed powder is completely sprayed, continuously rotating the main engine for 5min, stopping the main engine, taking out the prepared particles, and carrying out air blast drying at 40-50 ℃ to obtain slow-release;
3. preparing the theophylline sustained-release dry suspension: respectively pulverizing lactose, mannitol, sucrose and hydroxypropyl methylcellulose in the formula, sieving with 100 mesh sieve, mixing with the prepared sustained-release granules in a trough mixer for 20min, granulating with 18 mesh sieve using water as binder, drying at 40-50 deg.C, grading with 20 mesh sieve, spraying 0.1% essence, and mixing for 40min to obtain theophylline sustained-release dry suspension.
Example 3: preparation method 2 of theophylline sustained-release dry suspension
1. The preparation of the mother nucleus is carried out according to the preparation method in the invention;
2. preparation of sustained-release granules: respectively crushing theophylline and stearic acid in a formula, sieving the crushed theophylline and stearic acid with a 120-mesh sieve, uniformly mixing to prepare mixed powder, putting a mother nucleus in a centrifugal granulator, using a 3% methylcellulose aqueous solution as an adhesive, adjusting the rotating speed of a main engine to 180rpm/min, the blowing flow to 400rpm, the blowing pressure to 0.6Map, the blowing flow to 17L/min, the rotating speed of a blowing pump to 20rpm and the powder supply speed to 15rpm, carrying out slurry supply and powder supply until the mixed powder is completely sprayed, continuing rotating the main engine for 8min, stopping the main engine, taking out the prepared particles, and carrying out blowing drying at 60 ℃ to obtain slow-release particles;
3. preparing the theophylline sustained-release dry suspension: respectively pulverizing lactose, mannitol, sucrose and hydroxypropyl methylcellulose in the formula, sieving with 100 mesh sieve, mixing with the prepared sustained-release granules in a trough type mixer for 25min, granulating with 20 mesh sieve using water as binder, drying at 60 deg.C, grading with 20 mesh sieve, spraying 0.5% essence, and mixing for 60min to obtain theophylline sustained-release dry suspension. Example 4 preparation method 3 of theophylline sustained-release dry suspension
1. The preparation of the mother nucleus is carried out according to the preparation method in the invention;
2. preparation of sustained-release granules: respectively crushing theophylline and sodium dodecyl benzene sulfonate in a formula, sieving the crushed theophylline and sodium dodecyl benzene sulfonate with a 120-mesh sieve, uniformly mixing to prepare mixed powder, putting a mother nucleus in a centrifugal granulator, using a 3% hydroxypropyl methyl cellulose aqueous solution as an adhesive, adjusting the rotating speed of a main engine to 200rpm/min, the air blast flow to 450rpm, the air blast pressure to 0.6Map, the air blast flow to 20L/min, the rotating speed of a guniting pump to 25rpm and the powder supply speed to 20rpm, carrying out slurry supply and powder supply until the mixed powder is completely sprayed, continuing rotating the main engine for 8min, stopping the main engine, taking out the prepared particles, and carrying out air blast drying at 50 ℃ to obtain slow-;
3. preparing the theophylline sustained-release dry suspension: respectively pulverizing lactose, mannitol, sucrose and hydroxypropyl methylcellulose in the formula, sieving with 100 mesh sieve, mixing with the prepared sustained-release granules in a trough type mixer for 25min, granulating with 18 mesh sieve using water as binder, drying at 50 deg.C, grading with 18 mesh sieve, spraying 1% essence, and mixing for 60min to obtain theophylline sustained-release dry suspension.
Example 5 preparation method of theophylline sustained-release dry suspension 4
1. The preparation of the mother nucleus is carried out according to the preparation method in the invention;
2. preparation of sustained-release granules: respectively crushing theophylline and sodium dodecyl benzene sulfonate in a formula, sieving the crushed theophylline and sodium dodecyl benzene sulfonate with a 100-mesh sieve, uniformly mixing to prepare mixed powder, putting a mother nucleus in a centrifugal granulator, using a 2% hydroxypropyl cellulose aqueous solution as an adhesive, adjusting the rotating speed of a host machine to be 180rpm/min, the blast flow to be 350rpm, the air injection pressure to be 0.5Map, the air injection flow to be 15L/min, the rotating speed of a guniting pump to be 15rpm and the powder supply speed to be 10rpm, carrying out slurry supply and powder supply until the mixed powder is completely sprayed, continuing rotating the host machine for 5min, stopping the host machine, taking out the prepared particles, and carrying out blast drying at 40 ℃;
3. preparing the theophylline sustained-release dry suspension: respectively pulverizing lactose, mannitol, sucrose and hydroxypropyl methylcellulose in the formula, sieving with 100 mesh sieve, mixing with the prepared sustained-release granules in a trough mixer for 20min, granulating with 18 mesh sieve using water as binder, drying at 40 deg.C, grading with 20 mesh sieve, spraying 0.1% essence, and mixing for 40min to obtain theophylline sustained-release dry suspension.
Example 6 theophylline sustained Release Dry suspension sedimentation volume ratio test
According to the detection method of the sinking volume ratio of dry suspension items in the fourth part of the Chinese pharmacopoeia,
taking 20g of the slow-release dry suspension of the invention, placing the suspension in a 100ml measuring cylinder with a plug, adding 50ml of water, shaking forcefully for 1 minute, and recording the initial height H of the suspension0And keeping standing for 3 hours, recording the final height H of the suspension, and setting the volume ratio as follows: H/H0
By detection, H01.3mm, 1.23mm, and 0.946 in the sedimentation volume ratio of 1.23/1.3, and meets the standard requirements of Chinese pharmacopoeia.
Claims (6)
1. The preparation method of the theophylline slow-release dry suspension comprises 250g of 150-fold and 150-80 g of cellulose, a proper amount of adhesive, 30-40g of surfactant, 20-30g of lactose, 20-30g of mannitol, 500-700g of sucrose, 1-2% of hydroxypropyl methyl cellulose and 0.1-1% of essence, and is characterized in that the preparation method comprises the following steps:
(1) preparation of mother nucleus: placing cellulose in the formula into a centrifugal granulator, granulating with water as binder, drying at 40-60 deg.C, and collecting 40-60 mesh granules to obtain mother nucleus;
(2) preparation of sustained-release granules: respectively crushing theophylline and a surfactant in a formula, passing the crushed theophylline and the surfactant through a 120-mesh screen with 100 meshes, uniformly mixing to prepare mixed powder, putting a mother nucleus in a centrifugal granulator, using a 2-3% hydroxypropyl cellulose aqueous solution as an adhesive, adjusting the rotating speed of a host machine to be 180-mesh and 200rpm/min, the air blowing flow to be 350-mesh and 450rpm, the air blowing pressure to be 0.5-0.6Map, the air blowing flow to be 15-20L/min, the rotating speed of a slurry pump to be 15-25rpm and the powder supply speed to be 10-20rpm, carrying out slurry supply and powder supply until the mixed powder is completely sprayed, continuing rotating the host machine for 5-8min, stopping the host machine, taking out the prepared particles, and carrying out air blowing drying at 40-60 ℃ to obtain;
(3) preparing the theophylline sustained-release dry suspension: respectively pulverizing lactose, mannitol, sucrose and hydroxypropyl methylcellulose in the formula, sieving with 100 mesh sieve, mixing with the prepared sustained-release granules in a trough mixer for 20-25min, granulating with 18-20 mesh sieve using water as binder, drying at 40-60 deg.C, grading with 20 mesh sieve, spraying 0.1-1% essence, and mixing for 40-60min to obtain theophylline sustained-release dry suspension.
2. The method for preparing the theophylline sustained-release dry suspension according to claim 1, wherein the binder is one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose or methylcellulose.
3. The method for preparing the theophylline sustained-release dry suspension according to claim 1, wherein the surfactant is stearic acid, sodium dodecylbenzenesulfonate.
4. The process for preparing a theophylline sustained release dry suspension according to claim 1, wherein the binder is formulated with water into a 2-3% aqueous solution.
5. The method for preparing the theophylline sustained-release dry suspension according to claim 1, wherein the 1-2% hydroxypropyl methylcellulose is hydroxypropyl methylcellulose accounting for 1-2% of the total prescribed amount.
6. The method for preparing a theophylline sustained-release dry suspension according to claim 1, wherein the slurry supply and the powder supply are performed alternately after the slurry supply.
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