CN116019773A - Amlodipine besylate freeze-dried orally disintegrating tablet and preparation method thereof - Google Patents
Amlodipine besylate freeze-dried orally disintegrating tablet and preparation method thereof Download PDFInfo
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Abstract
The invention discloses an amlodipine besylate freeze-dried orally disintegrating tablet and a preparation method thereof, and is characterized in that the amlodipine besylate freeze-dried orally disintegrating tablet comprises amlodipine besylate, an adhesive, a framework supporting agent and a suspending agent, wherein the framework supporting agent is maltodextrin, and the suspending agent is acacia. The amlodipine besylate freeze-dried orally disintegrating tablet effectively solves the problem of tablet agglomeration caused by poor stability of amlodipine besylate as a raw material medicine and easy moisture absorption when meeting humidity, and the prepared tablet has good formability and excellent stability, and simultaneously the improvement of the preparation process ensures that all raw materials can be fully and uniformly mixed. The amlodipine besylate freeze-dried orally disintegrating tablet has the advantages of simple material, moderate tablet weight, difficult breaking, simple preparation process and suitability for industrial mass production.
Description
Technical Field
The invention relates to the field of oral preparations, in particular to an amlodipine besylate freeze-dried orally disintegrating tablet and a preparation method thereof.
Background
Along with the improvement of the living standard of people and the change of the dietary structure and the living style, the incidence rate of hypertension in recent years has gradually increased. Hypertension can cause damage to heart, brain, kidney and other organs of patients, has close relation with sugar and lipid metabolic disorder and diabetes, obviously reduces the life quality of the patients, and even endangers life when serious. Therefore, research on antihypertensive drugs is attracting more and more attention from scholars at home and abroad.
Amlodipine besylate is a common drug for treating hypertension and angina, is a calcium ion antagonist which directly acts on vascular smooth muscle to reduce peripheral vascular resistance, thereby reducing blood pressure; by expanding peripheral arterioles, peripheral resistance is reduced, so that myocardial oxygen consumption is reduced, and coronary arteries and coronary arterioles in normal and ischemic areas are expanded, so that myocardial oxygen supply of coronary artery spasticity patients is increased, and the purpose of relieving angina is achieved.
Compared with other tablet formulations, the amlodipine besylate is prepared into a freeze-dried orally disintegrating tablet which can be rapidly disintegrated or dissolved in the mouth without taking with water; a considerable part of the extract is absorbed through the oral cavity, so that the first pass effect of the liver is reduced; the orally disintegrating tablet disintegrates and disperses into fine particles rapidly before the medicine reaches the gastrointestinal tract, so that the problem of overlarge stimulation to the gastrointestinal tract caused by overhigh local concentration of the medicine in the gastrointestinal tract is avoided. However, due to the auxiliary material components, the preparation process and the like of the amlodipine besylate freeze-dried orally disintegrating tablet, the existing amlodipine besylate freeze-dried orally disintegrating tablet is easy to generate caking phenomenon, and the tablet is difficult to form and has poor stability.
In the preparation process of the amlodipine besylate freeze-dried orally disintegrating tablet, as the main component amlodipine besylate has poor stability, is easy to absorb moisture when meeting humidity, is sensitive to light and temperature, and the existing electrostatic effect can cause the phenomenon that the main component amlodipine besylate and various auxiliary materials in the amlodipine besylate freeze-dried orally disintegrating tablet are easy to aggregate or adhere to the inner wall of a container. Therefore, the selection of auxiliary materials in the amlodipine besylate freeze-dried orally disintegrating tablet is very critical.
Patent CN102525972a discloses a preparation method of amlodipine besylate orally disintegrating tablets: (a) preparation of matrix liquid: adding amlodipine besylate, glycine or mannitol or a mixture thereof, pullulan or sodium alginate or a mixture thereof, sweetener and aromatic into a fully dissolved solution of xanthan gum or konjac gum or a mixture thereof to form a uniform solution; (b) degassing; (c) injection molding; (d) pre-freezing; (e) And then transferring the mould into a freeze dryer, and freeze-drying for 1-10 hours under the pressure of 0.01 mbar-10 mbar and the temperature of minus 30 ℃ to obtain the amlodipine besylate orally disintegrating tablet.
The patent CN1546024A discloses an amlodipine besylate orally disintegrating tablet, the main medicine of which is amlodipine besylate, and the auxiliary materials comprise lactose, mannitol, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, crosslinked polyvinylpyrrolidone, sodium bicarbonate, citric acid, aspartame, essence and magnesium stearate.
However, the applicant found that by adopting the method of the prior art, when xanthan gum is selected as a suspending agent to be mixed with amlodipine besylate serving as a main drug, the agglomeration phenomenon of the amlodipine besylate freeze-dried orally disintegrating tablet can be caused; when mannitol or glycine is selected as a framework support agent to be mixed with amlodipine besylate serving as a main drug, the problem of poor tablet formability of the amlodipine besylate freeze-dried orally disintegrating tablet can be caused. Therefore, the amlodipine besylate freeze-dried orally disintegrating tablet which can avoid aggregation of main drugs and auxiliary materials to generate caking and improve the problem of tablet molding is an urgent problem to be solved.
Disclosure of Invention
The invention overcomes the defects of agglomeration, difficult forming of tablets, medicine liquid sticking, bottom sticking, edge cracking and concave tablet shape generated after aggregation of main medicine and auxiliary materials in the prior art, and provides a prescription and a preparation method of amlodipine besylate freeze-dried orally disintegrating tablet which can ensure uniform mixing of raw materials, good tablet formability and excellent stability.
The first aspect of the invention provides a freeze-dried orally disintegrating tablet, which comprises a pharmaceutical active ingredient, an adhesive, a framework support agent and a suspending agent, wherein the framework support agent is maltodextrin, and the suspending agent is acacia.
Further, the freeze-dried orally disintegrating tablet also comprises a sweetener or edible essence or a mixture of the sweetener and the edible essence.
Further, the pharmaceutically active ingredient in the lyophilized orally disintegrating tablet is selected from the group consisting of: amlodipine or a pharmaceutically acceptable salt or ester thereof, preferably amlodipine in a pharmaceutically acceptable salt.
Further, the amlodipine or pharmaceutically acceptable salt or ester thereof in the freeze-dried orally disintegrating tablet is selected from the group consisting of: amlodipine besylate, amlodipine mesylate, amlodipine L-aspartate, amlodipine camphorsulfonate, amlodipine nicotinate, amlodipine pyroglutamate, amlodipine gentisate, amlodipine lipoic acid and amlodipine maleate, preferably amlodipine besylate.
Further, the freeze-dried orally disintegrating tablet contains 0.01 to 2.0 parts by weight of amlodipine besylate, preferably 0.1 to 1.0 parts by weight of amlodipine besylate (such as 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9 and 1.0), and particularly preferably 0.693 parts by weight of amlodipine besylate.
Further, the freeze-dried orally disintegrating tablet contains 0.1 to 2.0 parts by weight of a binder, preferably 0.1 to 1.0 parts by weight of a binder (e.g., 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0), particularly preferably 0.8 parts by weight of a binder, wherein the binder is selected from the group consisting of: one or more of pullulan, alginate, hydroxypropyl methylcellulose, hyaluronic acid, modified starch, polyvinyl alcohol and chitosan, preferably, the binder is pullulan.
Further, the freeze-dried orally disintegrating tablet contains 1.0 to 10.0 parts by weight of maltodextrin, preferably 2.0 to 8.0 parts by weight of maltodextrin (e.g., 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0), and particularly preferably 5.0 parts by weight of maltodextrin.
Further, the lyophilized orally disintegrating tablet contains 0.01 to 2.0 parts by weight of acacia gum, preferably 0.01 to 1.0 parts by weight of acacia gum (e.g., 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0), particularly preferably 0.72 parts by weight of acacia gum.
Further, the freeze-dried orally disintegrating tablet contains 0.01 to 1.0 part by weight of a sweetener, preferably 0.01 to 0.5 part by weight of a sweetener (e.g., 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.2, 0.3, 0.4, 0.5), particularly preferably 0.1 part by weight of a sweetener, wherein the sweetener is selected from the group consisting of: one or more natural or synthetic sweeteners such as sucralose, aspartame, sodium saccharin, neotame, acesulfame potassium, aspartame, and sucrose, preferably, the sweetener is sucralose.
Further, the freeze-dried orally disintegrating tablet comprises 0.01 to 1.0 part by weight of edible essence, preferably 0.01 to 0.1 part by weight of edible essence (such as 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09 and 1.0) in the freeze-dried orally disintegrating tablet, particularly preferably 0.04 part by weight of edible essence in the freeze-dried orally disintegrating tablet, wherein the edible essence is selected from the group consisting of: one or more of peppermint essence, sweet orange essence, pineapple essence and strawberry essence, preferably, the edible essence is peppermint essence.
The amlodipine besylate freeze-dried orally disintegrating tablet is different from the existing prescription, and the existing prescription generally adopts glycine or mannitol as a framework supporting agent and xanthan gum or sodium alginate as a suspending agent, so that the problems of drug caking, difficult tablet forming, drug liquid sticking, edge cracking, tablet concave and the like cannot be effectively solved. The invention adopts maltodextrin as a framework supporting agent and Arabic gum as a suspending agent, which can ensure that all raw materials are uniformly mixed, further effectively avoid the phenomenon that amlodipine besylate as a main medicine is poor in stability and easy to absorb moisture when wet, and the existing electrostatic effect can cause aggregation and agglomeration with various auxiliary materials, so that the prepared tablet is good in formability and excellent in stability. Therefore, proper prescription composition and dosage proportion are selected, and the stability and the formability of the amlodipine besylate freeze-dried orally disintegrating tablet are critically affected.
In one embodiment of the present invention, the lyophilized orally disintegrating tablet comprises:
0.01-2.0 parts of amlodipine besylate;
0.1-2.0 parts of adhesive;
maltodextrin 1.0-10.0 parts;
0.01-2.0 parts of acacia;
0.01-0.5 part of sweetener;
0.01-1.0 part of edible essence.
In one embodiment of the present invention, the lyophilized orally disintegrating tablet comprises:
0.01-2.0 parts of amlodipine besylate;
0.1-2.0 parts of pullulan;
maltodextrin 1.0-10.0 parts;
0.01-2.0 parts of acacia;
0.01-0.5 part of sucralose;
0.01-1.0 part of peppermint essence.
In one embodiment of the present invention, the lyophilized orally disintegrating tablet unit dose comprises:
amlodipine besylate 6.93mg;
pullulan 8mg;
50mg of maltodextrin;
gum arabic 7.2mg;
1mg of sucralose;
peppermint essence 0.4mg.
The second aspect of the present invention provides a method for preparing the above freeze-dried orally disintegrating tablet, comprising the steps of:
(1) Weighing active ingredients of the medicines, an adhesive, maltodextrin and Arabic gum, adding water, and stirring to obtain a freeze-dried solution;
(2) Degassing the freeze-dried solution in the step (1);
(3) Injecting the freeze-dried solution subjected to the degassing in the step (2) into a mold;
(4) Carrying out freeze-drying molding on the mold filled with the freeze-drying solution in the step (3);
further, the pharmaceutically active ingredient in step (1) of the present invention is selected from: amlodipine or a pharmaceutically acceptable salt or ester thereof, preferably amlodipine in a pharmaceutically acceptable salt.
Further, the amlodipine or pharmaceutically acceptable salt or ester thereof is selected from the group consisting of: amlodipine besylate, amlodipine mesylate, amlodipine L-aspartate, amlodipine camphorsulfonate, amlodipine nicotinate, amlodipine pyroglutamate, amlodipine gentisate, amlodipine lipoic acid and amlodipine maleate, preferably amlodipine besylate.
Further, the adhesive in step (1) of the present invention is selected from: one or a combination of more than two of pullulan, alginate, hydroxypropyl methylcellulose, hyaluronic acid, modified starch, polyvinyl alcohol and chitosan, preferably the binder is pullulan.
Further, the active pharmaceutical ingredient in the step (1) is a bulk drug subjected to crushing treatment, and the crushing control particle size D90 is 10 mu m; the water adding step is divided into two steps, wherein the first step is to add 20% of the prescription amount of purified water at one time, and the second step is to gradually add water to 80% of the prescription amount of purified water; the heating is water bath heating, the temperature of the water bath heating is 30-50 ℃, the time is 20-40min, preferably the temperature of the water bath heating is 35-45 ℃, the time is 25-35min, more preferably the temperature of the water bath heating is 40 ℃, and the time is 30min; the stirring is homogenizing shearing stirring, the rotating speed of homogenizing shearing is 2000-8000 r/min, the homogenizing shearing time is 2-15 min, preferably, the rotating speed of homogenizing shearing is 2000-4000 r/min, the homogenizing shearing time is 2-10 min, more preferably, the rotating speed of homogenizing shearing is 2500r/min, and the homogenizing shearing time is 30min.
Further, the degassing treatment in the step (2) is to transfer the sample solution into a degassing bottle, and vacuum degassing is performed until no bubbles are generated.
Further, the freeze-drying and forming in the step (4) of the invention comprises pre-freezing for 3-15 min at-40 to-80 ℃, preferably pre-freezing for 3-10 min at-50 to-70 ℃. More preferably, the pre-frozen is at-60℃for 5min.
Further, before the freeze-drying and forming in the step (4), the method comprises the following steps: setting the initial freeze-drying temperature at-30 ℃, putting the pre-frozen bubble cap plate into a freeze-drying box, setting the cold trap temperature at-40 ℃ to-60 ℃, and setting the vacuum degree at 10-60 pa, preferably 20-30pa; setting the temperature of the plate layer: raising the temperature from-30 ℃ to-5 ℃ for 25 minutes; maintaining the temperature at-5 ℃ for 120 minutes; raising the temperature from-5 ℃ to 25 ℃ for 30 minutes.
The second aspect of the present invention also provides another preparation method of the above freeze-dried orally disintegrating tablet, which comprises the following steps:
(1) Weighing active ingredients of the medicines, an adhesive, maltodextrin and Arabic gum, adding water, stirring, heating, cooling to room temperature, adding sweetener and edible essence, and stirring to obtain a freeze-dried solution;
(2) Degassing the freeze-dried solution in the step (1);
(3) Injecting the freeze-dried solution subjected to the degassing in the step (2) into a mold;
(4) And (3) carrying out freeze-drying molding on the mold filled with the freeze-drying solution in the step (3).
Further, the pharmaceutically active ingredient in step (1) of the present invention is selected from: amlodipine or a pharmaceutically acceptable salt or ester thereof, preferably amlodipine in a pharmaceutically acceptable salt.
Further, the amlodipine or pharmaceutically acceptable salt or ester thereof is selected from the group consisting of: amlodipine besylate, amlodipine mesylate, amlodipine L-aspartate, amlodipine camphorsulfonate, amlodipine nicotinate, amlodipine pyroglutamate, amlodipine gentisate, amlodipine lipoic acid and amlodipine maleate, preferably amlodipine besylate.
Further, the adhesive in step (1) of the present invention is selected from: one or a combination of more than two of pullulan, alginate, hydroxypropyl methylcellulose, hyaluronic acid, modified starch, polyvinyl alcohol and chitosan, preferably the binder is pullulan.
Further, the sweetener in step (1) of the present invention is selected from: one or more natural or synthetic sweeteners such as sucralose, aspartame, sodium saccharin, neotame, acesulfame potassium, aspartame, and sucrose, preferably, the sweetener is sucralose.
Further, the flavoring essence in the step (1) is selected from the group consisting of: one or more of peppermint essence, sweet orange essence, pineapple essence and strawberry essence, preferably, the edible essence is peppermint essence.
Further, the active pharmaceutical ingredient in the step (1) is a bulk drug subjected to crushing treatment, and the crushing control particle size D90 is 10 mu m; the water adding step is divided into two steps, wherein the first step is to add 20% of the prescription amount of purified water at one time, and the second step is to gradually add water to 80% of the prescription amount of purified water; the heating is water bath heating, the temperature of the water bath heating is 30-50 ℃, the time is 20-40min, preferably the temperature of the water bath heating is 35-45 ℃, the time is 25-35min, more preferably the temperature of the water bath heating is 40 ℃, and the time is 30min; the stirring is homogenizing shearing stirring, the rotating speed of homogenizing shearing is 2000-8000 r/min, the homogenizing shearing time is 2-15 min, preferably, the rotating speed of homogenizing shearing is 2000-4000 r/min, the homogenizing shearing time is 2-10 min, more preferably, the rotating speed of homogenizing shearing is 2500r/min, and the homogenizing shearing time is 30min.
Further, the degassing treatment in the step (2) is to transfer the sample solution into a degassing bottle, and vacuum degassing is performed until no bubbles are generated.
Further, the freeze-drying and forming in the step (4) of the invention comprises pre-freezing for 3-15 min at-40 to-80 ℃, preferably pre-freezing for 3-10 min at-50 to-70 ℃. More preferably, the pre-frozen is at-60℃for 5min.
Further, before the freeze-drying and forming in the step (4), the method comprises the following steps: setting the initial freeze-drying temperature at-30 ℃, putting the pre-frozen bubble cap plate into a freeze-drying box, setting the cold trap temperature at-40 ℃ to-60 ℃, and setting the vacuum degree at 10-60 pa, preferably 20-30pa; setting the temperature of the plate layer: raising the temperature from-30 ℃ to-5 ℃ for 25 minutes; maintaining the temperature at-5 ℃ for 120 minutes; raising the temperature from-5 ℃ to 25 ℃ for 30 minutes.
In one embodiment of the present invention, the method for preparing the freeze-dried orally disintegrating tablet comprises the following steps:
(1) Weighing amlodipine besylate, pullulan, maltodextrin and acacia, adding water, stirring, heating, cooling to room temperature, adding sucralose and peppermint essence, and stirring to obtain a freeze-dried solution;
(2) Degassing the freeze-dried solution in the step (1);
(3) Injecting the freeze-dried solution subjected to the degassing in the step (2) into a mold;
(4) And (3) carrying out freeze-drying molding on the mold filled with the freeze-drying solution in the step (3).
Further, the amlodipine besylate in the step (1) is a bulk drug which is subjected to crushing treatment, and the crushing control particle size D90 is 10 mu m; the water adding step is divided into two steps, wherein the first step is to add 20% of the prescription amount of purified water at one time, and the second step is to gradually add water to 80% of the prescription amount of purified water; the heating is water bath heating, the temperature of the water bath heating is 30-50 ℃, the time is 20-40min, preferably the temperature of the water bath heating is 35-45 ℃, the time is 25-35min, more preferably the temperature of the water bath heating is 40 ℃, and the time is 30min; the stirring is homogenizing shearing stirring, the rotating speed of homogenizing shearing is 2000-8000 r/min, the homogenizing shearing time is 2-15 min, preferably, the rotating speed of homogenizing shearing is 2000-4000 r/min, the homogenizing shearing time is 2-10 min, more preferably, the rotating speed of homogenizing shearing is 2500r/min, and the homogenizing shearing time is 30min.
Further, the degassing treatment in the step (2) is to transfer the sample solution into a degassing bottle, and vacuum degassing is performed until no bubbles are generated.
Further, the freeze-drying and forming in the step (4) of the invention comprises pre-freezing for 3-15 min at-40 to-80 ℃, preferably pre-freezing for 3-10 min at-50 to-70 ℃. More preferably, the pre-frozen is at-60℃for 5min.
Further, before the freeze-drying and forming in the step (4), the method comprises the following steps: setting the initial freeze-drying temperature at-30 ℃, putting the pre-frozen bubble cap plate into a freeze-drying box, setting the cold trap temperature at-40 ℃ to-60 ℃, and setting the vacuum degree at 10-60 pa, preferably 20-30pa; setting the temperature of the plate layer: raising the temperature from-30 ℃ to-5 ℃ for 25 minutes; maintaining the temperature at-5 ℃ for 120 minutes; raising the temperature from-5 ℃ to 25 ℃ for 30 minutes.
The invention improves the formulation and the preparation process of the amlodipine besylate freeze-dried orally disintegrating tablet. The formulation of the preparation effectively solves the problem of tablet caking caused by poor stability of amlodipine besylate as a raw material drug and easy moisture absorption when meeting humidity, and ensures that the tablet has better formability and excellent stability; compared with other preparation processes, the particle size D90 of the amlodipine besylate is obviously reduced, and the amlodipine besylate serving as a raw material is dry-mixed uniformly with each auxiliary material and then added with water, and the water is added twice, so that the raw materials can be fully and uniformly mixed; the amlodipine besylate freeze-dried orally disintegrating tablet has small volume, is convenient to take, can disintegrate or dissolve in saliva without being taken with water, and is especially suitable for the old, children, dysphagia patients and water inconvenient patients to take; the bioavailability is high, and a considerable part of the extract is absorbed through the oral cavity, so that the first pass effect of the liver is avoided; the gastrointestinal tract is fast in absorption, and the medicine can be rapidly disintegrated and dispersed into fine particles before reaching the gastrointestinal tract, so that the medicine is distributed in a large area in the gastrointestinal tract, the absorption points are increased, and the absorption speed of the medicine in the gastrointestinal tract is greatly improved; the amlodipine besylate freeze-dried orally disintegrating tablet has the advantages of simple material, moderate tablet weight, difficult breaking, simple preparation process and suitability for industrial mass production.
Drawings
Fig. 1 is a schematic front view of a lyophilized orally disintegrating tablet product prepared according to prescription 1, wherein both the left and right tablets are front views of the lyophilized orally disintegrating tablet product.
Fig. 2 is a schematic back view of a lyophilized orally disintegrating tablet product prepared according to prescription 1, wherein both the left and right tablets are back views of the lyophilized orally disintegrating tablet product.
Fig. 3 is a schematic front view of a lyophilized orally disintegrating tablet product prepared according to prescription 2, wherein both the left and right tablets are front views of the lyophilized orally disintegrating tablet product.
Fig. 4 is a schematic back view of a lyophilized orally disintegrating tablet product prepared according to prescription 2, wherein both the left and right tablets are back views of the lyophilized orally disintegrating tablet product.
Fig. 5 is a schematic front view of a lyophilized orally disintegrating tablet product prepared according to prescription 3, wherein both the left and right tablets are front views of the lyophilized orally disintegrating tablet product.
Fig. 6 is a schematic back view of a lyophilized orally disintegrating tablet product prepared according to prescription 3, wherein both the left and right tablets are back views of the lyophilized orally disintegrating tablet product.
Fig. 7 is a schematic front view of a lyophilized orally disintegrating tablet product prepared according to prescription 4, wherein both the left and right tablets are front views of the lyophilized orally disintegrating tablet product.
Fig. 8 is a schematic back view of a freeze-dried orally disintegrating tablet product of amlodipine besylate prepared according to formula 4, wherein both the left and right tablets are back views of the freeze-dried orally disintegrating tablet product.
Fig. 9 is a schematic front view of a freeze-dried orally disintegrating tablet product of amlodipine besylate prepared according to formula 5, wherein both the left and right tablets are front views of the freeze-dried orally disintegrating tablet product.
Fig. 10 is a schematic back view of a freeze-dried orally disintegrating tablet product of amlodipine besylate prepared according to formula 5, wherein both the left and right tablets are back views of the freeze-dried orally disintegrating tablet product.
Detailed Description
In order that the technical content of the present invention may be more clearly understood, the following detailed description of the embodiments is given only for better understanding of the content of the present invention and is not intended to limit the scope of the present invention. The reagents used in the examples of the present invention are all commercially available. The scoring criteria for the freeze-dried orally disintegrating tablets in the examples of the present invention are as follows: 5+ is full, and 4+ and above are qualified.
EXAMPLE 1 examination of the Effect of Using acacia in the formulation as a suspending agent on amlodipine besylate lyophilized orally disintegrating tablets
1.1 preparation method of amlodipine besylate freeze-dried orally disintegrating tablets
Amlodipine besylate freeze-dried orally disintegrating tablets were prepared according to the following table.
(1) Weighing the prescription amount of maltodextrin, pullulan, arabic gum and crude drugs (the crushing grain diameter D90 is controlled to be 10 mu m) in a 100ml shearing cup, adding 20% of prescription amount of purified water for stirring after dry mixing, gradually adding 80% of prescription amount of purified water, carrying out water bath at 40 ℃ for 30min, cooling to room temperature, adding the prescription amount of sucralose and mint essence, and stirring for dissolution;
(2) The volume is fixed, namely the sample solution is respectively fixed to the total weight of each prescription;
(3) Shearing: the rotation speed is 2500rpm, and the time is 30min;
(4) Degassing: transferring the sample solution into a degassing bottle, and vacuumizing and degassing until no bubbles are generated;
(5) Filling and pre-freezing: injecting samples by a liquid-transferring gun, wherein the sample injection amount is 0.4 g/piece, and placing the aluminum-plastic bubble cap after sample injection into a low-temperature preservation box at-60 ℃ for pre-freezing;
(6) And (3) freeze-drying: the initial temperature of lyophilization was set at-30 ℃, and the pre-frozen blister plates were placed into a lyophilization oven. The specific freeze-drying setting parameters are as follows:
cold trap temperature: -40 ℃ to-60 ℃; vacuum control: 20-30pa;
ply temperature: raising the temperature from-30 ℃ to-5 ℃ for 25 minutes; maintaining the temperature at-5 ℃ for 120 minutes;
raising the temperature from-5 ℃ to 25 ℃ for 30 minutes.
| Name of the name | Action | Prescription 1 |
| API | Active ingredient | 0.693g |
| Pullulan polysaccharide | Adhesive agent | 0.8g |
| Maltodextrin | Framework agent | 5g |
| Glycine (Gly) | Framework agent | / |
| Mannitol (mannitol) | Framework agent | / |
| Acacia gum | Suspending agent | 720mg |
| Sodium alginate | Suspending agent | / |
| Xanthan gum | Suspending agent | / |
| Sucralose | Flavoring agent | 100mg |
| Peppermint essence | Flavoring agent | 40mg |
| Child haha purified water | Solvent(s) | / |
| Total weight of | / | 40.0g |
1.2 experimental results
| Prescription of prescription | Prescription 1 |
| Intermediate solution | 5+ |
| Appearance of | 5+ |
| Wall sticking | 4+ |
| Disintegration of | 5+ |
Comparative example 1 investigation of the Effect of sodium alginate or xanthan gum as suspending agent on amlodipine besylate lyophilized orally disintegrating tablets
1.1 preparation method of amlodipine besylate freeze-dried orally disintegrating tablets
Amlodipine besylate freeze-dried orally disintegrating tablets were prepared according to the following table.
(1) Weighing the prescription amount of maltodextrin, pullulan, sodium alginate or xanthan gum and raw materials (crushing to control the particle diameter D90 to be 10 mu m) in a 100ml shearing cup, adding 20% of prescription amount of purified water for stirring after dry mixing, gradually adding 80% of prescription amount of purified water, carrying out water bath for 30min at 40 ℃, cooling to room temperature, adding the prescription amount of sucralose and mint essence, and stirring for dissolution;
(2) The volume is fixed, namely the sample solution is respectively fixed to the total weight of each prescription;
(3) Shearing: the rotation speed is 2500rpm, and the time is 30min;
(4) Degassing: transferring the sample solution into a degassing bottle, and vacuumizing and degassing until no bubbles are generated;
(5) Filling and pre-freezing: injecting samples by a liquid-transferring gun, wherein the sample injection amount is 0.4 g/piece, and placing the aluminum-plastic bubble cap after sample injection into a low-temperature preservation box at-60 ℃ for pre-freezing;
(6) And (3) freeze-drying: the initial temperature of lyophilization was set at-30 ℃, and the pre-frozen blister plates were placed into a lyophilization oven. The specific freeze-drying setting parameters are as follows:
cold trap temperature: -40 ℃ to-60 ℃; vacuum control: 20-30pa;
ply temperature: raising the temperature from-30 ℃ to-5 ℃ for 25 minutes; maintaining the temperature at-5 ℃ for 120 minutes;
raising the temperature from-5 ℃ to 25 ℃ for 30 minutes.
| Name of the name | Action | Prescription 2 | Prescription 3 |
| API | Active ingredient | 0.693g | 0.693g |
| Pullulan polysaccharide | Adhesive agent | 0.8g | 0.8g |
| Maltodextrin | Framework agent | 5g | 5g |
| Glycine (Gly) | Framework agent | / | / |
| Mannitol (mannitol) | Framework agent | / | / |
| Acacia gum | Suspending agent | / | / |
| Sodium alginate | Suspending agent | 720mg | / |
| Xanthan gum | Suspending agent | / | 720mg |
| Sucralose | Flavoring agent | 100mg | 100mg |
| Peppermint essence | Flavoring agent | 40mg | 40mg |
| Child haha purified water | Solvent(s) | / | / |
| Total weight of | / | 40.0g | 40.0g |
1.2 experimental results
| Prescription of prescription | Prescription 2 | Prescription 3 |
| Intermediate solution | Easy sedimentation | With masses |
| Appearance of | 4+ | 3+ |
| Wall sticking | 5+ | 2+ |
| Disintegration of | 5+ | 5+ |
Comparative example 2 examination of the influence of the use of glycine or mannitol as a matrix support on amlodipine besylate lyophilized orally disintegrating tablets when the suspending agent was acacia
2.1 preparation method of amlodipine besylate freeze-dried orally disintegrating tablets
Amlodipine besylate freeze-dried orally disintegrating tablets were prepared according to the following table.
(1) Weighing the prescription amount of glycine or mannitol, pullulan, acacia and crude drugs (the crushing grain diameter D90 is controlled to be 10 mu m) in a 100ml shearing cup, adding 20% of prescription amount of purified water for stirring after dry mixing, gradually adding 80% of prescription amount of purified water, carrying out water bath at 40 ℃ for 30min, cooling to room temperature, adding the prescription amount of sucralose and mint essence, and stirring for dissolution;
(2) The volume is fixed, namely the sample solution is respectively fixed to the total weight of each prescription;
(3) Shearing: the rotation speed is 2500rpm, and the time is 30min;
(4) Degassing: transferring the sample solution into a degassing bottle, and vacuumizing and degassing until no bubbles are generated;
(5) Filling and pre-freezing: injecting samples by a liquid-transferring gun, wherein the sample injection amount is 0.4 g/piece, and placing the aluminum-plastic bubble cap after sample injection into a low-temperature preservation box at-60 ℃ for pre-freezing;
(6) And (3) freeze-drying: the initial temperature of lyophilization was set at-30 ℃, and the pre-frozen blister plates were placed into a lyophilization oven. The specific freeze-drying setting parameters are as follows:
cold trap temperature: -40 ℃ to-60 ℃; vacuum control: 20-30pa;
ply temperature: raising the temperature from-30 ℃ to-5 ℃ for 25 minutes; maintaining the temperature at-5 ℃ for 120 minutes;
raising the temperature from-5 ℃ to 25 ℃ for 30 minutes.
| Name of the name | Action | Prescription 4 | Prescription 5 |
| API | Active ingredient | 0.693g | 0.693g |
| Pullulan polysaccharide | Adhesive agent | 0.8g | 0.8g |
| Maltodextrin | Framework agent | / | / |
| Glycine (Gly) | Framework agent | 5g | / |
| Mannitol (mannitol) | Framework agent | / | 5g |
| Acacia gum | Suspending agent | 720mg | 720mg |
| Sodium alginate | Suspending agent | / | / |
| Xanthan gum | Suspending agent | / | / |
| Sucralose | Flavoring agent | 100mg | 100mg |
| Peppermint essence | Flavoring agent | 40mg | 40mg |
| Child haha purified water | Solvent(s) | / | / |
| Total weight of | / | 40.0g | 40.0g |
2.2 experimental results
| Prescription of prescription | Prescription 4 | Prescription 5 |
| Intermediate solution | 5+ | 5+ |
| Appearance of | 2+ | 3+ |
| Wall sticking | 2+ | 2+ |
| Disintegration of | 5+ | 5+ |
As is clear from the comparison of example 1 and comparative example 1, when sodium alginate is used as a suspending agent, the intermediate solution is liable to sedimentation and the tablet appearance is general; when xanthan gum is used as a suspending agent, the intermediate solution has lumps and the tablet appearance is poor, so gum arabic is selected as the suspending agent. As is clear from comparative example 1 and comparative example 2, when glycine or mannitol is used as a matrix support, the tablet exhibits a severe wall sticking phenomenon and the tablet has a poor appearance, and thus maltodextrin is used as the matrix support. By comparing the whole of the embodiment 1 with the whole of the comparative embodiment 1-2, the problem of tablet agglomeration caused by poor stability and easy moisture absorption of the raw material drug amlodipine besylate when the maltodextrin is adopted as a framework supporting agent and the Arabic gum is adopted as a suspending agent can be greatly improved by the compound prescription of the maltodextrin and the Arabic gum, and the problems of poor formability, wall adhesion, poor appearance and the like of the tablet are simultaneously overcome.
Claims (12)
1. The freeze-dried orally disintegrating tablet is characterized by comprising a medicinal active ingredient, an adhesive, a framework supporting agent and a suspending agent, wherein the framework supporting agent is maltodextrin, and the suspending agent is acacia.
2. A lyophilized orally disintegrating tablet according to claim 1, wherein the lyophilized orally disintegrating tablet further comprises a sweetener or a flavoring or a mixture of a sweetener and a flavoring.
3. A lyophilized orally disintegrating tablet according to claim 1 or 2, wherein the pharmaceutically active ingredient is selected from the group consisting of: amlodipine or a pharmaceutically acceptable salt or ester thereof, preferably amlodipine in a pharmaceutically acceptable salt.
4. A lyophilized orally disintegrating tablet according to claim 3, wherein the amlodipine or pharmaceutically acceptable salt or ester thereof is selected from the group consisting of: amlodipine besylate, amlodipine mesylate, amlodipine L-aspartate, amlodipine camphorsulfonate, amlodipine nicotinate, amlodipine pyroglutamate, amlodipine gentisate, amlodipine lipoic acid and amlodipine maleate, preferably amlodipine besylate.
5. The lyophilized orally disintegrating tablet according to claim 4, wherein the lyophilized orally disintegrating tablet comprises 0.01 to 2.0 parts by weight of amlodipine besylate, preferably 0.1 to 1.0 parts by weight of amlodipine besylate, and particularly preferably 0.693 parts by weight of amlodipine besylate.
6. A lyophilized orally disintegrating tablet according to claim 1 or 2, wherein the lyophilized orally disintegrating tablet comprises 0.1 to 2.0 parts by weight of a binder, preferably 0.1 to 1.0 parts by weight of a binder, particularly preferably 0.8 parts by weight of a binder, wherein the binder is selected from the group consisting of: one or more of pullulan, alginate, hydroxypropyl methylcellulose, hyaluronic acid, modified starch, polyvinyl alcohol and chitosan, preferably, the binder is pullulan.
7. A lyophilized orally disintegrating tablet according to claim 1 or 2, wherein the lyophilized orally disintegrating tablet comprises 1.0 to 10.0 parts by weight of maltodextrin, preferably 2.0 to 8.0 parts by weight of maltodextrin, and particularly preferably 5.0 parts by weight of maltodextrin.
8. The amlodipine besylate freeze-dried orally disintegrating tablet according to claim 1 or 2, wherein the freeze-dried orally disintegrating tablet comprises 0.01 to 2.0 parts by weight of acacia gum, preferably 0.01 to 1.0 parts by weight of acacia gum, and particularly preferably 0.72 parts by weight of acacia gum.
9. A lyophilized orally disintegrating tablet according to claim 2, wherein the lyophilized orally disintegrating tablet comprises 0.01 to 1.0 parts by weight of a sweetener, preferably 0.01 to 0.5 parts by weight of a sweetener, particularly preferably 0.1 parts by weight of a sweetener, wherein the sweetener is selected from the group consisting of: one or more natural or synthetic sweeteners such as sucralose, aspartame, sodium saccharin, neotame, acesulfame potassium, aspartame, and sucrose, preferably, the sweetener is sucralose.
10. The freeze-dried orally disintegrating tablet according to claim 2, wherein the freeze-dried orally disintegrating tablet comprises 0.01 to 1.0 part by weight of edible essence, preferably 0.01 to 0.1 part by weight of edible essence, and particularly preferably 0.04 part by weight of edible essence, wherein the edible essence is selected from the group consisting of: one or more of peppermint essence, sweet orange essence, pineapple essence and strawberry essence, preferably, the edible essence is peppermint essence.
11. The lyophilized orally disintegrating tablet of claim 4, wherein the preparation method of the lyophilized orally disintegrating tablet comprises:
(1) Weighing active ingredients of the medicines, an adhesive, maltodextrin and Arabic gum, adding water, and stirring to obtain a freeze-dried solution;
(2) Degassing the freeze-dried solution in the step (1);
(3) Injecting the freeze-dried solution subjected to the degassing in the step (2) into a mold;
(4) Carrying out freeze-drying molding on the mold filled with the freeze-drying solution in the step (3);
the pharmaceutical active ingredient is selected from the group consisting of: amlodipine or a pharmaceutically acceptable salt or ester thereof, preferably a pharmaceutically acceptable salt of amlodipine; the amlodipine or the pharmaceutically acceptable salt or ester thereof is selected from the following components: the combination of one or more of amlodipine besylate, amlodipine mesylate, amlodipine L-aspartate, amlodipine camphorsulfonate, amlodipine nicotinate, amlodipine pyroglutamate, amlodipine gentisate, amlodipine lipoic acid and amlodipine maleate is preferably amlodipine besylate; the adhesive is selected from the group consisting of: one or more of pullulan, alginate, hydroxypropyl methylcellulose, hyaluronic acid, modified starch, polyvinyl alcohol and chitosan, preferably, the binder is pullulan.
12. The lyophilized orally disintegrating tablet of claim 2, wherein the preparation method of the lyophilized orally disintegrating tablet comprises:
(1) Weighing active ingredients of the medicines, an adhesive, maltodextrin and Arabic gum, adding water, stirring, heating, cooling to room temperature, adding sweetener and edible essence, and stirring to obtain a freeze-dried solution;
(2) Degassing the freeze-dried solution in the step (1);
(3) Injecting the freeze-dried solution subjected to the degassing in the step (2) into a mold;
(4) Carrying out freeze-drying molding on the mold filled with the freeze-drying solution in the step (3);
the pharmaceutical active ingredient is selected from the group consisting of: amlodipine or a pharmaceutically acceptable salt or ester thereof, preferably a pharmaceutically acceptable salt of amlodipine; the amlodipine or the pharmaceutically acceptable salt or ester thereof is selected from the following components: the combination of one or more of amlodipine besylate, amlodipine mesylate, amlodipine L-aspartate, amlodipine camphorsulfonate, amlodipine nicotinate, amlodipine pyroglutamate, amlodipine gentisate, amlodipine lipoic acid and amlodipine maleate is preferably amlodipine besylate; the adhesive is selected from the group consisting of: one or more of pullulan, alginate, hydroxypropyl methylcellulose, hyaluronic acid, modified starch, polyvinyl alcohol and chitosan, preferably, the binder is pullulan; the sweetener is selected from the following components: one or more natural or synthetic sweeteners such as sucralose, aspartame, saccharin sodium, neotame, acesulfame potassium, aspartame, and sucrose, preferably, the sweetener is sucralose; the edible essence is selected from the following components: one or more of peppermint essence, sweet orange essence, pineapple essence and strawberry essence, preferably, the edible essence is peppermint essence.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202111254686.3A CN116019773A (en) | 2021-10-27 | 2021-10-27 | Amlodipine besylate freeze-dried orally disintegrating tablet and preparation method thereof |
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| Application Number | Priority Date | Filing Date | Title |
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| CN202111254686.3A CN116019773A (en) | 2021-10-27 | 2021-10-27 | Amlodipine besylate freeze-dried orally disintegrating tablet and preparation method thereof |
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