CN115282124A - Glipizide controlled release tablet and preparation method thereof - Google Patents
Glipizide controlled release tablet and preparation method thereof Download PDFInfo
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Abstract
The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a glipizide controlled release tablet and a preparation method thereof. The glipizide controlled release tablet comprises a drug-containing layer, a propulsion layer, a controlled release film and a soluble film; the medicine-containing layer comprises glipizide, polyvidone, sodium chloride, polyethylene glycol, hypromellose, red ferric oxide, and magnesium stearate; the propelling layer comprises polyvidone, sodium carboxymethylcellulose, hydroxypropyl cellulose, sodium chloride, red ferric oxide, magnesium stearate, hydroxypropyl methylcellulose, 95% ethanol and purified water; the controlled release film coating solution comprises cellulose acetate, polyethylene glycol, purified water and acetone; the soluble film coating liquid comprises gastric soluble film coating premix and purified water. The glipizide controlled release tablet of the invention conforms to the zero-order drug release model of the controlled release tablet, is not influenced by the pH value in vivo and the gastrointestinal environment, improves the treatment effect and the compliance of patients, has the quality and the treatment effect which are consistent with the quality and the treatment effect of the original product, and has high production efficiency and low energy consumption.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a glipizide controlled release tablet and a preparation method thereof.
Background
Osmotic pump type controlled release tablets are a production technology of oral solid preparations emerging in the pharmaceutical industry in recent years, and are gradually advocated by the market due to the specific technical advantages and treatment advantages of the oral solid preparations.
The osmotic pump type controlled release tablet is prepared by fully mixing the drug with entrainer, osmotic pressure regulator and the like to prepare drug-containing layer particles, preparing a double-layer tablet core (drug-containing layer and boosting layer) together with the additionally prepared boosting layer particles by adopting a double-layer tabletting technology, coating the tablet core by cellulose acetate and the like to form a rigid semipermeable membrane (which only allows water to permeate in the body and hardly changes the shape after taking and in the drug release process), finally forming a drug release pore on the membrane by laser, and then coating a moisture-proof layer.
The prior double-chamber osmotic pump product mostly uses various types of polyethylene oxide (PEO) as main filling agent and entrainer during preparation, mainly because the product has good plasticity and is easy to be tabletted and formed, and the hydration speed of the product is moderate after the product is orally taken; the product prepared by other substitute materials is often obviously different from the original medicine in biological equivalence. In the production mode, wet granulation, dry granulation, fluidized bed one-step granulation or mixing direct compression and the like are mostly adopted for granulation. However, the use of PEO as a key adjunct has the following disadvantages:
(1) The source is single, the acquisition is difficult, most models have short validity period, and the storage is difficult. At present, the material is prepared by unique production and has a single source channel. Due to the product characteristics and poor stability, the validity period of individual models is only 6 months, while the import goods period is often as long as 3-4 months, which is not favorable for stable production and supply in pharmaceutical factories.
(2) The stability is not good, which is not beneficial to continuous commercial production. PEO is unstable to heat and greatly influenced by production conditions, and has a typical glass transition temperature of about 60 ℃, but since it is a high molecular polymer, the actual polymerization degree is not uniform, and there is a large difference in properties between the components. In the actual use process, the production temperature is found to be over 40 ℃, and the physical properties begin to change; the polymer chains begin to break or polymerize beyond 60 ℃.
(3) During the production process, PEO is used for granulation, and no matter which granulation mode is adopted, the local temperature of equipment and materials is increased due to extrusion and friction, so that part of the materials are denatured to form a plastic-like tough substance, and the product quality is affected; in addition, in the tabletting process, due to end jumping and friction heating of tabletting equipment, the material melting phenomenon in the tabletting process occurs after continuous production is carried out for 3-4 hours, so that the problems of poor material flowability, abnormal piece weight difference, poor smoothness of the piece surface and the like are caused; potential quality problems can also result during the encapsulation process due to the short heat seal temperatures of up to 160 c.
In addition, the long-term high temperature possibly existing in the long-term processes of transportation, circulation, use and storage during coating and after marketing is not favorable for the stability of the product quality.
(4) High price and high production cost. Because the material belongs to foreign imported materials and only one legal supplier exists, the supply of the material is in monopoly status, and the price is high and is 800-2000 yuan/kg. In order to ensure the consistency of the quality of the domestic medicine and the quality of the original medicine, the osmotic pump products are produced by adopting the materials, and the materials are the key auxiliary materials with the largest dosage, so that the cost of the auxiliary materials even exceeds the cost of the raw material medicines, and the production cost of the medicine is high.
Therefore, the method has urgent needs of reasonable substitution with low cost, excellent performance and sufficient material supply and solves a series of problems in the continuous production process.
Disclosure of Invention
The technical problem to be solved by the invention is as follows: the glipizide controlled release tablet provided accords with a zero-order drug release model of the controlled release tablet, is not influenced by the pH value in vivo and the gastrointestinal environment, improves the treatment effect and the patient compliance, and has the quality and the treatment effect consistent with those of the original medicine; the invention also provides a preparation method of the high-efficiency high-stability high-strength polyester resin, which improves the production efficiency, reduces the energy consumption and improves the product stability.
The glipizide controlled release tablet comprises a drug-containing layer, a propulsion layer, a controlled release film and a soluble film;
wherein the drug-containing layer comprises: glipizide, povidone, sodium chloride, polyethylene glycol, hypromellose, red iron oxide, magnesium stearate;
the propulsion layer includes: povidone, sodium carboxymethylcellulose, hydroxypropyl cellulose, sodium chloride, red ferric oxide, magnesium stearate, hydroxypropyl methylcellulose, 95% ethanol and purified water;
the coating solution of the controlled release film adopted by the controlled release film comprises: cellulose acetate, polyethylene glycol, purified water, acetone;
the soluble film coating solution adopted by the soluble film comprises: gastric soluble film coating premix and purified water.
When the glipizide controlled release tablet is prepared, firstly, a hot melting method is adopted to prepare drug-containing layer particles, wet mixing is adopted to prepare push layer particles, then the drug-containing layer and the push layer are prepared into a double-layer, then, controlled release film coating is carried out until the weight of the double-layer is increased by 7-10%, single hole making is carried out on one side of the drug-containing layer of the controlled release film, a punched controlled release film coated tablet is obtained, and finally, soluble film coating is carried out until the weight of the controlled release film coated tablet is increased by 7.5-8.5%, thus obtaining the glipizide controlled release tablet.
Preferably, the medicine-containing layer comprises the following raw materials in parts by weight:
preferably, the propelling layer comprises the following raw materials in parts by weight:
preferably, the controlled release film coating solution adopted by the controlled release film comprises the following raw materials in parts by weight:
preferably, the soluble film coating solution adopted by the soluble film comprises the following raw materials in parts by weight:
10-25 parts of gastric-soluble film coating premix,
90-125 parts of purified water.
The gastric-soluble film coating premix is prepared from a commercially available product.
Wherein, the povidone is used in the medicine-containing layer and the propelling layer, and the povidone has better fluidity and stability, stronger bonding effect, higher molecular weight and stronger viscosity, and forms viscous gel when meeting water. The functional characteristics can partially replace the main function of polyoxyethylene N80 in the original medicine, and the functional characteristics are used as an entrainer of the medicine-containing layer and are used as the main component of the medicine-containing layer; can also play the role of a propellant in the propelling layer and maintain the overall shape and the continuous propelling capability of the propelling layer. The goal of partial replacement of the PEO function can also be achieved.
Hydroxypropyl cellulose is used in the boosting layer, a model with high viscosity is selected as a hydrophilic gel framework material, and forms viscous gel and generates volume expansion after meeting water, so that the boosting layer provides a relatively long-lasting propelling force. The goal of partial replacement of PEO functions can be achieved.
Hypromellose is used in the drug-containing layer and the push layer, and functions as an adhesive. Cellulose auxiliary materials such as povidone, hydroxypropyl cellulose and the like have longer molecular chains, the deformation of the cellulose auxiliary materials in the tabletting process is elastic deformation, and a tablet with good hardness can be prepared only by applying larger main pressure. By adding the hydroxypropyl methylcellulose, the compressibility of the material can be increased, the equal compressibility of PEO is realized, and the tablet strength of the drug-containing layer and the propelling layer is increased.
The carboxymethyl cellulose sodium is used in the propelling layer, the conventional function of the auxiliary material is a disintegrating agent, and the auxiliary material can rapidly and obviously expand in volume after meeting water, and can partially replace the expansion function of PEO.
The preparation method of the glipizide controlled release tablet comprises the following steps:
(1) Preparing medicine-containing layer particles:
mixing glipizide, povidone, sodium chloride, polyethylene glycol, hydroxypropyl methylcellulose and red ferric oxide according to the prescription of a medicine-containing layer, heating at 60-70 ℃ for 1-2h, granulating and finishing when the mixture is hot, and then uniformly mixing granules after finishing and magnesium stearate according to the prescription to obtain medicine-containing layer granules;
(2) Preparing particles of a propulsion layer:
mixing povidone, sodium carboxymethylcellulose, hydroxypropyl cellulose, sodium chloride, red iron oxide, hydroxypropyl methylcellulose, 95% ethanol and purified water according to the prescription amount of the propulsion layer, granulating, drying, finishing, and then uniformly mixing the granules with the prescription amount of magnesium stearate to obtain propulsion layer granules;
(3) Double-layer tablet pressing:
pressing the medicine-containing layer particles and the propelling layer particles by a double-layer tablet high-speed tablet press to obtain a double-layer tablet, wherein the thickness ratio of the medicine-containing layer to the propelling layer is 2:1-3:2;
(4) Coating with a controlled release film:
uniformly mixing cellulose acetate, polyethylene glycol, purified water and acetone according to the prescription amount of the controlled release film coating solution to obtain a controlled release film coating solution, coating the double tablets, finishing coating after the weight of the coating is increased by 7-10%, and drying to obtain a controlled release film coated tablet;
(5) Laser drilling:
performing laser drilling on the controlled release film-coated tablet, and performing single drilling on one side of the drug-containing layer of the tablet, wherein the aperture is 0.5-1.0mm, so as to obtain the drilled controlled release film-coated tablet;
(6) Curing, drying and coating a water-soluble film:
according to the prescription amount of the soluble film coating solution, uniformly mixing the gastric soluble film coating premix and purified water to obtain the soluble coating solution, coating the perforated controlled release film coating tablet, finishing coating after the coating is increased by 7.5-8.5%, and drying to obtain the glipizide controlled release tablet.
Preferably, when laser drilling is carried out, the laser output power is set to be 68%, the laser frequency is set to be 10KHz, the distance between the center position of the hole and the center relative position of the tablet is +/-1.5 mm, the drilling depth is indirectly controlled by setting the numerical values of the laser frequency and the laser output power, and the best is to just drill the controlled release film coating.
The glipizide controlled release tablet prepared by the invention is an osmotic pump tablet, and the tablet comprises a double-layer tablet consisting of a drug-containing layer and a propelling layer, wherein the outer surface of the double-layer tablet is coated with a controlled release film and a soluble film, and the controlled release film is provided with laser micropores (drug release micropores).
The structure of the double-layer tablet of the osmotic pump tablet is changed before and during the release of the drug as shown in figure 1. After the patient takes the product, water enters the tablet through the rigid semipermeable membrane under the action of osmotic pressure, the propellant layer propellant expands to form thrust, which becomes the power for releasing the drug, and the drug suspension after water absorption is pushed out from the drug release micropores. Because the used rigid semipermeable membrane is non-malleable, the volume in the membrane is always kept constant, and the existence of the osmotic pressure regulator (sodium chloride) enables the osmotic pressure to be kept stable, the medicine can be continuously released, and the effect of releasing the medicine at a constant speed is achieved. The process of constant-speed drug release follows the following zero-order drug release formula:
(dm/dt)＝(KA/h)×π s ×S d ；
wherein dm/dt is the release speed of the drug, K is the permeability coefficient of the coating film to water, A and h are the area and thickness of the coating film, and pi s Is the osmotic pressure in the tablet core, S d Is the solubility of the drug.
Because the osmotic pump tablet coating film is rigid, the internal volume is fixed, the osmotic pressure inside the coated tablet is basically constant due to the existence of osmotic pressure regulator (sodium chloride), and the solubility of the medicine is constant. Therefore, the release process of the oral osmotic pump tablet is zero-order release in a certain time, and the release process is continued until the drug in the coating film is completely released.
According to the structural principle, after oral administration, the product is only influenced by the internal prescription structure and osmotic pressure, but not by the change of release environment, pH value and other factors in the gastrointestinal tract, can be released at a constant speed for a long time, and reduces the frequency of administration and the fluctuation of blood concentration, thereby achieving better clinical curative effect.
Compared with the prior art, the invention has the following beneficial effects:
(1) The glipizide controlled release tablet of the double-chamber osmotic pump adopts a drug release model of the double-chamber osmotic pump, particularly adopts easily obtained common materials to replace expensive and single-source materials PEO in the preparation process, simultaneously solves the problems of supply and instability of key auxiliary materials, and greatly reduces the prescription cost;
(2) According to the invention, a hot-melt preparation mode is used in the granulating process, so that the organic solvent residue in the granulating process is reduced, the production efficiency is improved, the energy consumption is reduced, the equipment investment is reduced, and the like;
(3) According to the invention, multi-step transfer of materials is avoided in the granulating process, dust is reduced by thermal adhesion, material loss is reduced, the yield is higher than 99%, and compared with common dry granulating and wet granulating, the production efficiency is improved by about 4 times;
(4) The double-chamber osmotic pump propulsion layer is used, so that the coloring agent can be solidified, and the problem of color mixing in the pressing process of the double-layer tablet is effectively solved;
(5) According to the invention, the laser drilling mode with low power is adopted, the drilling effect is intelligently judged, the service life of a laser is prolonged, the use and maintenance of equipment are facilitated, the product quality is improved, and the problem of tablet time lag is relieved;
(6) The invention obtains more uniform and stable products by improving and controlling the procedures of coating, laser drilling and the like, and the products conform to a zero-order drug release model of the controlled release tablet through in vitro tests and clinical bioequivalence tests.
Drawings
FIG. 1 is a schematic diagram showing the structural change of a double-layer tablet before and during drug release of an osmotic pump tablet according to the present invention;
FIG. 2 is an in vitro dissolution test (pH 1.2 hydrochloric acid solution) of the product of example 1 of the present invention with a reference formulation;
FIG. 3 is an in vitro dissolution test (pH 4.5 acetate buffer) of the product of example 1 of the present invention with a reference formulation;
FIG. 4 is a graph of the in vitro dissolution test (pH 6.8 phosphate buffer) of the product of example 1 of the present invention with a reference formulation;
FIG. 5 is a graph showing an in vitro dissolution test (pH 7.5 phosphate buffer) of the product of example 1 of the present invention with a reference formulation.
Detailed Description
The present invention is further illustrated by the following examples, but the scope of the present invention is not limited thereto, and modifications of the technical solutions of the present invention by those skilled in the art should be within the scope of the present invention.
The starting materials used in the examples are, unless otherwise specified, commercially available conventional starting materials; the processes used in the examples are, unless otherwise specified, conventional in the art.
Example 1
The prescription of the medicine-containing layer is as follows:
5.5mg of glipizide, 67mg of povidone, 15mg of sodium chloride, 10mg of polyethylene glycol, 5mg of hydroxypropyl methylcellulose, 0.03mg of red ferric oxide and 0.1mg of magnesium stearate.
The push layer formulation was as follows:
40mg of povidone, 9mg of sodium carboxymethyl cellulose, 30mg of hydroxypropyl cellulose, 20mg of sodium chloride, 0.6mg of red iron oxide, 0.1mg of magnesium stearate, 0.53mg of hydroxypropyl methylcellulose, 9.6mg of 95% ethanol and 1.07mg of purified water.
The coating solution of the controlled release film adopted by the controlled release film has the following formula:
20mg of cellulose acetate, 15mg of polyethylene glycol, 13mg of purified water and 500mg of acetone.
The formula of the soluble film coating solution adopted by the soluble film is as follows:
gastric-soluble film coating premix (SNWW-012, new Phil biopharmaceutical engineering Co., ltd., shanghai) 19mg, and purified water 101mg.
The preparation method comprises the following steps:
(1) Preparing medicine-containing layer particles:
mixing glipizide, povidone, sodium chloride, polyethylene glycol, hydroxypropyl methylcellulose and red ferric oxide according to the prescription amount of a medicine-containing layer, putting the mixture into an oven, setting the temperature of the oven to be 70 ℃, heating the mixture for 1h, adding the hot material into a swing granulator for granulation, transferring the hot material into a granulator for dry granulation, feeding the granules and the magnesium stearate in the prescription amount into a mixer for uniform mixing to obtain medicine-containing layer granules;
(2) Preparing particles of a propulsion layer:
adding povidone, sodium carboxymethylcellulose, hydroxypropyl cellulose, sodium chloride, red iron oxide and hydroxypropyl methylcellulose into a mixing granulator according to the prescription amount of the propulsion layer, spraying a granulating solution prepared from 95% ethanol and purified water to prepare a propulsion layer soft material, discharging, transferring to a fluidized bed for drying, performing dry granulation on the dried propulsion layer particles, transferring to a mixing machine, adding magnesium stearate according to the prescription amount, and uniformly mixing to obtain propulsion layer particles;
(3) Double-layer tablet pressing:
adopting a double-layer tablet high-speed tablet press, wherein the punch specification is as follows: the inner diameter of the shallow recess is 8mm, the particles of the drug-containing layer and the particles of the propelling layer are respectively loaded into hoppers with corresponding marks, the filling amount is adjusted according to the weight range of the tablet, the thickness ratio of the drug-containing layer to the propelling layer is controlled to be 2:1, and the total tablet thickness is 4.2mm;
(4) Coating with a controlled release film:
uniformly mixing cellulose acetate, polyethylene glycol, purified water and acetone according to the prescription amount of the controlled-release film coating solution to obtain a controlled-release film coating solution, placing the qualified double-layer tablets in a high-efficiency coating machine, coating by adopting a high-efficiency coating technology, controlling the coating weight to be increased by 10% according to the release requirement, closing and heating after the coating is finished, drying for 1 hour, and discharging to obtain a controlled-release film coated tablet;
(5) Laser drilling:
the controlled release film coated tablet is punched by laser, a single hole is formed in one side of a drug-containing layer of the tablet, the aperture is 0.5mm, the laser output power is set to be 68%, the laser frequency is set to be 10KHz, the distance between the center position of the hole and the center of the tablet is +/-1.5 mm, the punching depth is indirectly controlled by setting the numerical value of the laser frequency and the laser output power, the controlled release film coating is punched just optimally, and the punched controlled release film coated tablet is obtained;
(6) Curing, drying and coating a water-soluble film:
uniformly mixing a gastric-soluble film coating premix and purified water according to the prescription amount of a soluble film coating solution to obtain the soluble coating solution, placing a perforated controlled release film coating tablet in a high-efficiency coating machine, drying and curing for 12 hours, carrying out water-soluble coating, mainly aiming at preventing moisture of a product, finishing coating when the coating is increased by 8%, drying for 1 hour, and then discharging to obtain the glipizide controlled release tablet.
Example 2
The prescription of the medicine-containing layer is as follows:
5mg of glipizide, 45mg of povidone, 10mg of sodium chloride, 5mg of polyethylene glycol, 5mg of hydroxypropyl methylcellulose, 0.03mg of red ferric oxide and 0.1mg of magnesium stearate.
The push layer formulation was as follows:
30mg of povidone, 5mg of sodium carboxymethyl cellulose, 15mg of hydroxypropyl cellulose, 15mg of sodium chloride, 0.6mg of red iron oxide, 0.1mg of magnesium stearate, 0.53mg of hydroxypropyl methylcellulose, 8mg of 95% ethanol and 1mg of purified water.
The coating solution of the controlled release film adopted by the controlled release film has the following formula:
10mg of cellulose acetate, 25mg of polyethylene glycol, 10mg of purified water and 550mg of acetone.
The formula of the soluble film coating solution adopted by the soluble film is as follows:
25mg of gastric-soluble film coating premix (SNWW-012, new Phil biopharmaceutical engineering Co., ltd., shanghai) and 125mg of purified water.
The preparation method comprises the following steps:
(1) Preparing medicine-containing layer particles:
mixing glipizide, povidone, sodium chloride, polyethylene glycol, hydroxypropyl methylcellulose and red ferric oxide according to the prescription amount of the drug-containing layer, putting the mixture into an oven, setting the temperature of the oven to be 60 ℃, heating the mixture for 2 hours, adding the hot material into a swing granulator for granulation, transferring the hot material into a granulator for dry granulation, feeding the granules and the magnesium stearate in the prescription amount into a mixer for uniform mixing to obtain drug-containing layer granules;
(2) Preparing particles of a propulsion layer:
adding povidone, sodium carboxymethylcellulose, hydroxypropyl cellulose, sodium chloride, red iron oxide and hydroxypropyl methylcellulose into a mixing granulator according to the prescription amount of the propulsion layer, spraying a granulating solution prepared from 95% ethanol and purified water to prepare a propulsion layer soft material, discharging, transferring to a fluidized bed for drying, performing dry granulation on the dried propulsion layer particles, transferring to a mixing machine, adding magnesium stearate according to the prescription amount, and uniformly mixing to obtain propulsion layer particles;
(3) Double-layer tablet pressing:
adopting a double-layer tablet high-speed tablet press, wherein the punch specification is as follows: the inner diameter of the shallow recess is 8mm, the particles of the drug-containing layer and the particles of the propelling layer are respectively loaded into hoppers with corresponding marks, the filling amount is adjusted according to the weight range of the tablet, the thickness ratio of the drug-containing layer to the propelling layer is controlled to be 3:2, and the total tablet thickness is 4.2mm;
(4) Coating with a controlled release film:
uniformly mixing cellulose acetate, polyethylene glycol, purified water and acetone according to the prescription amount of the controlled-release film coating solution to obtain a controlled-release film coating solution, placing the qualified double-layer tablets in a high-efficiency coating machine, coating by adopting a high-efficiency coating technology, controlling the weight of the coating to be increased by 7 percent according to the release requirement, closing and heating after the coating is finished, drying for 1 hour, and discharging to obtain a controlled-release film coating tablet;
(5) Laser drilling:
the controlled release film coated tablet is punched by laser, a single hole is formed in one side of a drug-containing layer of the tablet, the aperture is 1.0mm, the laser output power is set to be 68%, the laser frequency is set to be 10KHz, the distance between the center position of the hole and the center of the tablet is +/-1.5 mm, the punching depth is indirectly controlled by setting the numerical value of the laser frequency and the laser output power, the controlled release film coating is punched just optimally, and the punched controlled release film coated tablet is obtained;
(6) Curing, drying and coating a water-soluble film:
uniformly mixing a gastric-soluble film coating premix and purified water according to the prescription amount of the soluble film coating solution to obtain the soluble coating solution, placing the perforated controlled release film coated tablet in a high-efficiency coating machine, drying and curing for 12 hours, carrying out water-soluble coating, mainly aiming at preventing moisture of a product, finishing coating when the coating is increased by 8.5%, drying for 1 hour, and discharging to obtain the glipizide controlled release tablet.
Example 3
The prescription of the medicine-containing layer is as follows:
6mg of glipizide, 100mg of povidone, 20mg of sodium chloride, 20mg of polyethylene glycol, 12mg of hydroxypropyl methylcellulose, 0.03mg of red ferric oxide and 0.1mg of magnesium stearate.
The push layer formulation was as follows:
povidone 70mg, carboxymethylcellulose sodium 20mg, hyprolose 40mg, sodium chloride 30mg, red iron oxide 0.6mg, magnesium stearate 0.1mg, hypromellose 0.8mg,95% ethanol 9.6mg, and purified water 1.07mg.
The coating solution of the controlled release film adopted by the controlled release film has the following formula:
25mg of cellulose acetate, 10mg of polyethylene glycol, 20mg of purified water and 400mg of acetone.
The formula of the soluble film coating solution adopted by the soluble film is as follows:
10mg of gastric-soluble film coating premix (SNWW-012, new Phil biopharmaceutical engineering Co., ltd., shanghai) and 90mg of purified water.
The preparation method comprises the following steps:
(1) Preparing medicine-containing layer particles:
mixing glipizide, povidone, sodium chloride, polyethylene glycol, hydroxypropyl methylcellulose and red ferric oxide according to the prescription of a medicine-containing layer, putting the mixture into an oven, setting the temperature of the oven to 65 ℃, heating for 1.5h, adding the hot material into a swing granulator for granulation, transferring the material into a granulator for dry granulation, feeding the granules and the magnesium stearate according to the prescription into a mixer, and uniformly mixing to obtain medicine-containing layer granules;
(2) Preparing particles of a propulsion layer:
adding povidone, sodium carboxymethylcellulose, hydroxypropyl cellulose, sodium chloride, red iron oxide and hydroxypropyl methylcellulose into a mixing granulator according to the prescription amount of the propulsion layer, spraying a granulating solution prepared from 95% ethanol and purified water to prepare a propulsion layer soft material, discharging, transferring to a fluidized bed for drying, performing dry granulation on the dried propulsion layer particles, transferring to a mixing machine, adding magnesium stearate according to the prescription amount, and uniformly mixing to obtain propulsion layer particles;
(3) Double-layer tablet pressing:
adopting a double-layer tablet high-speed tablet press, wherein the punch specification is as follows: the inner diameter of the shallow recess is 8mm, the particles of the drug-containing layer and the particles of the propelling layer are respectively loaded into hoppers with corresponding marks, the filling amount is adjusted according to the weight range of the tablet, the thickness ratio of the drug-containing layer to the propelling layer is controlled to be 2:1, and the total tablet thickness is 4.2mm;
(4) Coating with a controlled release film:
uniformly mixing cellulose acetate, polyethylene glycol, purified water and acetone according to the prescription amount of the controlled-release film coating solution to obtain a controlled-release film coating solution, placing the qualified double-layer tablets in a high-efficiency coating machine, coating by adopting a high-efficiency coating technology, controlling the weight of the coating to be increased by 8% according to the release requirement, closing and heating after the coating is finished, drying for 1 hour, and discharging to obtain a controlled-release film coating tablet;
(5) Laser drilling:
the controlled release film coated tablet is punched by laser, a single hole is formed in one side of a drug-containing layer of the tablet, the aperture is 0.8mm, the laser output power is set to be 68%, the laser frequency is set to be 10KHz, the distance between the center position of the hole and the center of the tablet is +/-1.5 mm, the punching depth is indirectly controlled by setting the numerical value of the laser frequency and the laser output power, the controlled release film coating is punched just optimally, and the punched controlled release film coated tablet is obtained;
(6) Curing, drying and coating a water-soluble film:
uniformly mixing a gastric-soluble film coating premix and purified water according to the prescription amount of the soluble film coating solution to obtain the soluble coating solution, placing the perforated controlled release film coated tablet in a high-efficiency coating machine, drying and curing for 12 hours, carrying out water-soluble coating, mainly aiming at preventing moisture of a product, finishing coating when the coating is increased by 7.5%, drying for 1 hour, and discharging to obtain the glipizide controlled release tablet.
Example 4
The prescription of the medicine-containing layer is as follows:
5.5mg of glipizide, 72mg of povidone, 15mg of sodium chloride, 12mg of polyethylene glycol, 7mg of hydroxypropyl methylcellulose, 0.03mg of red ferric oxide and 0.1mg of magnesium stearate.
The push layer formulation was as follows:
50mg of povidone, 12mg of sodium carboxymethyl cellulose, 28mg of hydroxypropyl cellulose, 22mg of sodium chloride, 0.6mg of red ferric oxide, 0.1mg of magnesium stearate, 0.53mg of hydroxypropyl methylcellulose, 9.6mg of 95% ethanol and 1.07mg of purified water.
The coating solution of the controlled release film adopted by the controlled release film has the following formula:
18mg of cellulose acetate, 15mg of polyethylene glycol, 13mg of purified water and 500mg of acetone.
The formula of the soluble film coating solution adopted by the soluble film is as follows:
gastric-soluble film coating premix (SNWW-012, new Phil biopharmaceutical engineering Co., ltd., shanghai) 18mg, and purified water 101mg.
The preparation method comprises the following steps:
(1) Preparing medicine-containing layer particles:
mixing glipizide, povidone, sodium chloride, polyethylene glycol, hydroxypropyl methylcellulose and red ferric oxide according to the prescription amount of a medicine-containing layer, putting the mixture into an oven, setting the temperature of the oven to be 70 ℃, heating the mixture for 1h, adding the hot material into a swing granulator for granulation, transferring the hot material into a granulator for dry granulation, feeding the granules and the magnesium stearate in the prescription amount into a mixer for uniform mixing to obtain medicine-containing layer granules;
(2) Preparing particles of a propulsion layer:
adding povidone, sodium carboxymethylcellulose, hydroxypropyl cellulose, sodium chloride, red iron oxide and hydroxypropyl methylcellulose into a mixing granulator according to the prescription amount of the propulsion layer, spraying a granulating solution prepared from 95% ethanol and purified water to prepare a propulsion layer soft material, discharging, transferring to a fluidized bed for drying, performing dry granulation on the dried propulsion layer particles, transferring to a mixing machine, adding magnesium stearate according to the prescription amount, and uniformly mixing to obtain propulsion layer particles;
(3) Double-layer tablet pressing:
adopting a double-layer tablet high-speed tablet press, wherein the punch specification is as follows: the inner diameter of the shallow recess is 8mm, the particles of the drug-containing layer and the particles of the propelling layer are respectively loaded into hoppers with corresponding marks, the filling amount is adjusted according to the weight range of the tablet, the thickness ratio of the drug-containing layer to the propelling layer is controlled to be 3:2, and the total tablet thickness is 4.2mm;
(4) Coating with a controlled release film:
uniformly mixing cellulose acetate, polyethylene glycol, purified water and acetone according to the prescription amount of the controlled-release film coating solution to obtain a controlled-release film coating solution, placing the qualified double-layer tablets in a high-efficiency coating machine, coating by adopting a high-efficiency coating technology, controlling the weight of the coated tablet to be increased by 9% according to the release requirement, closing the heating after the coating is finished, drying for 1 hour, and discharging to obtain a controlled-release film coated tablet;
(5) Laser drilling:
the controlled release film coated tablet is punched by laser, a single hole is formed in one side of a drug-containing layer of the tablet, the aperture is 0.5mm, the laser output power is set to be 68%, the laser frequency is set to be 10KHz, the distance between the center position of the hole and the center of the tablet is +/-1.5 mm, the punching depth is indirectly controlled by setting the numerical value of the laser frequency and the laser output power, the controlled release film coating is punched just optimally, and the punched controlled release film coated tablet is obtained;
(6) Curing, drying and coating a water-soluble film:
uniformly mixing a gastric-soluble film coating premix and purified water according to the prescription amount of a soluble film coating solution to obtain the soluble coating solution, placing a perforated controlled release film coating tablet in a high-efficiency coating machine, drying and curing for 12 hours, carrying out water-soluble coating, mainly aiming at preventing moisture of a product, finishing coating when the coating is increased by 8%, drying for 1 hour, and then discharging to obtain the glipizide controlled release tablet.
Comparative example 1
The comparative example adopts the same medicine prescription as that of example 1, and is different only in that when the medicine-containing layer particles are prepared in the step (1), the temperature of an oven is set to be 90 ℃, and the particles are heated for 1 hour; the rest of the procedure was the same as in example 1.
Comparative example 2
This comparative example used the same pharmaceutical formulation as in example 1, except that conventional wet granulation was used in the preparation of the drug-containing layer granules in step (1); setting the aperture to be 1.2mm when performing laser drilling in the step (5); the rest of the procedure was the same as in example 1.
Comparative example 3
The comparative example differs from example 1 only in that the propellant layer is dry blended, and the propellant layer formulation is: 40mg of povidone, 9mg of sodium carboxymethyl cellulose, 30mg of hydroxypropyl cellulose, 20mg of sodium chloride, 0.6mg of red ferric oxide, 0.1mg of magnesium stearate and 0.53mg of hydroxypropyl methylcellulose; the preparation method of the particles of the propulsion layer comprises the following steps: adding povidone, sodium carboxymethylcellulose, hydroxypropyl cellulose, sodium chloride, red ferric oxide and hydroxypropyl methylcellulose into a mixer according to the prescription of the propulsion layer, adding magnesium stearate according to the prescription, and uniformly mixing to obtain propulsion layer powder; the rest steps are the same as the embodiment.
Comparative example 4
This comparative example used the same drug formulation as in example 1, except that the weight gain of the coating was controlled to be 5% when the controlled release film coating was prepared in step (4); the rest of the procedure was the same as in example 1.
Comparative example 5
This comparative example used the same drug formulation as in example 1, except that the weight gain of the coating was controlled to be 12% when the controlled release film coating was prepared in step (4); the rest of the procedure was the same as in example 1.
Comparative example 6
The difference between the formulation of the present comparative example and example 1 is that neither the drug-containing layer nor the propellant layer formulation contains hydroxypropyl methylcellulose; the preparation method is the same as that of example 1.
Comparative example 7
The drug formulation of this comparative example differs from example 1 only in that the propellant layer formulation does not contain hydroxypropylcellulose; the preparation method is the same as that of example 1.
The glipizide controlled release tablets prepared in each example and comparative example were compared in quality with the original drug (lot No. DL 4766) as a reference formulation. The test results are shown in tables 1-2.
Table 1 comparison of quality parameters for the examples
Table 2 comparative example quality parameter comparison
As can be seen from tables 1-2:
examples 1-4 compared to the original drug, the in vitro experimental data was almost the same as the original drug, showing excellent quality consistency.
Comparative example 1, the heating temperature of the drug layer particles is increased, and the sum of single impurities, other impurities and other impurities is obviously increased when the detection is carried out, and although the limit is not exceeded, the overall adverse trend is obvious; in addition, the solidification in the production process is eliminated, and the residue of acetone is obviously increased and exceeds the specified limit.
Comparative example 2, the drug layer was granulated by wet method and the pore size was increased to 1.2mm, and the release was detected to be accelerated in 4 and 8 hours, wherein 8 hours release exceeded the limit, and the average release rate did not reach the ideal zero-order release, presumably due to the increased pore size of the perforations, leading to the forward release; in addition, significant increases in ethanol residue occurred, probably because the drug layer was wet granulated, introducing additional ethanol residue.
Comparative example 3, the push layer is mixed by a dry method, the powder is produced by a direct-compression mode, the overall release of the medicine is slow when the detection is carried out, wherein the release within 16 hours cannot meet the specified requirement, meanwhile, the average release speed within 8-12 hours is lower than the limit, and magnesium stearate is supposed to be directly mixed during granulation, and the hydration speed of the tablet core is slow due to the hydrophobicity of the magnesium stearate to influence the release; in addition, the content uniformity is obviously increased and exceeds the limit, which indicates that the flowability of the powder is not good, and the uniformity of tabletting is not good; in addition, the content is obviously reduced, so that disqualification is caused, probably because the granularity of the main drug is smaller, the granularity of the auxiliary material is large, and because granulation is not carried out, the loss of the main material in each procedure before tabletting is larger.
Comparative example 4, in comparison to the original drug, in vitro experimental data with multiple indicators beyond the limits of the standard limits, wherein the content is slightly below the lower limit of 105%; 4. the dissolution rate is too high in 8 hours, the average release rate is too fast in the early stage and weak in the later stage, and the lower limit of the average release rate is just reached in 8-12 hours, which is caused by that the controlled release film is too thin.
Comparative example 5, the content of the original drug is higher than the upper limit of 115%; the dissolution rate is too low in 4 hours, and the dissolution rate is too high after 8 hours, so that the average release rate at the later stage is too high, the ideal zero-order release cannot be achieved, and the controlled release film is caused by too thick coating.
Comparative example 6, due to lack of adhesion of hypromellose, compressibility of the material was relatively poor, extruded plain tablets were of a smaller weight, and tableting deviation was relatively large, so that content uniformity was significantly increased, indicating that the quality difference in batches was large and uneven, the overall release of the drug was slowed, and the content was slightly below the lower limit of 105%.
Comparative example 7, compared with the original drug, the in vitro experimental data completely meet the standard, but the dissolution rate is relatively high in 4 hours and low in 8 hours, so that the average release rate is relatively high in the early stage, the average rate is relatively low in the later stage, and the product cannot reach ideal zero-order release, probably because the high-viscosity hydroxypropylcellulose is absent in the propulsion layer, the propulsion layer cannot effectively provide durable propulsion.
In addition, the most important control item of the glipizide controlled release tablet is the release rate, and the in vitro release rate of the product of the example 1 of the invention and the original product is compared at different pH values.
Selection of a dissolution medium: according to the 'determination of dissolution curve of common oral solid preparation and comparative guiding principle', a medium with pH1.2, a medium with pH4.5, a medium with pH6.8 and a medium with pH7.5 are selected as in-vitro contrast dissolution media. The results of the similarity of dissolution curves of the product of example 1 of the present invention and the original drug are shown in FIGS. 2-5.
As can be seen from fig. 2-5, the self-formulation prepared by the present invention has a dissolution similarity factor f2=88 with the reference formulation in ph1.2 medium; dissolution similarity factor f2=94 in ph4.5 medium; dissolution similarity factor f2=73 in ph6.8 medium; the similar dissolution factor f2=81 in the medium with pH7.5 is greatly higher than the limit of 50, which can fully show that the dissolution curves of the self-made preparation and the reference preparation in the media with different pH values are similar to those of the original medicine.
The bioequivalence test was performed using the self-made glipizide controlled release tablet (lot No. 20201126) produced in example 1 of the present invention as the test formulation and the original yuelianning imported product (lot No. DL 4766) as the reference formulation, and the results of the bioequivalence test in the fasting state of random, open, two-formulation, single dose, two-cycle crossover in healthy subjects are shown in tables 3-4.
TABLE 3 pharmacokinetic parameters
TABLE 4 bioequivalence test results
The results in tables 3 to 4 show that the glipizide controlled release tablets (specification: 5 mg) produced by the present invention and the glipizide controlled release tablets (manufactured by Pfizer Pharmaceuticals LLC: (see)
Specification: 5 mg) and is bioequivalent by testing bioequivalence tests. The test results show that the tested preparation and the reference preparation
The safety in Chinese healthy subjects is good.
Claims (8)
1. The glipizide controlled release tablet is characterized in that: comprises a medicine-containing layer, a propulsion layer, a controlled release film and a soluble film;
wherein the drug-containing layer comprises: glipizide, povidone, sodium chloride, polyethylene glycol, hypromellose, red iron oxide, magnesium stearate;
the propulsion layer includes: povidone, sodium carboxymethylcellulose, hydroxypropyl cellulose, sodium chloride, red ferric oxide, magnesium stearate, hydroxypropyl methylcellulose, 95% ethanol and purified water;
the coating solution of the controlled release film adopted by the controlled release film comprises: cellulose acetate, polyethylene glycol, purified water, acetone;
the soluble film coating solution adopted by the soluble film comprises: gastric-soluble film coating premix and purified water;
when the glipizide controlled release tablet is prepared, firstly, a hot melting method is adopted to prepare drug-containing layer particles, wet mixing is adopted to prepare push layer particles, then the drug-containing layer and the push layer are prepared into a double-layer, then, controlled release film coating is carried out until the weight of the double-layer is increased by 7-10%, single hole making is carried out on one side of the drug-containing layer of the controlled release film, a punched controlled release film coated tablet is obtained, and finally, soluble film coating is carried out until the weight of the controlled release film coated tablet is increased by 7.5-8.5%, thus obtaining the glipizide controlled release tablet.
2. The glipizide controlled release tablet of claim 1, wherein: the medicine-containing layer comprises the following raw materials in parts by weight:
5-6 parts of glipizide,
45-100 parts of polyvidone, namely,
10-20 parts of sodium chloride, namely,
5-20 parts of polyethylene glycol,
1-12 parts of hydroxypropyl methylcellulose, wherein,
0.01 to 0.12 portion of red ferric oxide,
0.1-0.3 part of magnesium stearate.
3. The glipizide controlled release tablet of claim 1, wherein: the propelling layer comprises the following raw materials in parts by weight:
30-70 parts of polyvidone,
5-20 parts of sodium carboxymethyl cellulose,
15-40 parts of hydroxypropyl cellulose, and the like,
15-30 parts of sodium chloride, namely sodium chloride,
0.1 to 0.8 portion of red ferric oxide,
0.1 to 0.3 portion of magnesium stearate,
0.2 to 0.8 portion of hydroxypropyl methylcellulose,
8-12 parts of 95% ethanol,
0.5-5 parts of purified water.
4. The glipizide controlled release tablet of claim 1, wherein: the controlled release film coating solution adopted by the controlled release film comprises the following raw materials in parts by weight:
10-25 parts of cellulose acetate, and a solvent,
10-25 parts of polyethylene glycol,
10-20 parts of purified water, namely,
400-550 parts of acetone.
5. The glipizide controlled release tablet of claim 1, wherein: the soluble film coating solution adopted by the soluble film comprises the following raw materials in parts by weight:
10-25 parts of gastric soluble film coating premix,
90-125 parts of purified water.
6. A method for preparing glipizide controlled release tablets according to any one of claims 1 to 5, which is characterized in that: the method comprises the following steps:
(1) Preparing medicine-containing layer particles:
mixing glipizide, povidone, sodium chloride, polyethylene glycol, hydroxypropyl methylcellulose and red ferric oxide according to the prescription amount of the drug-containing layer, heating at 60-70 ℃ for 1-2h, granulating and finishing the granules when the granules are hot, and then uniformly mixing the granules after finishing the granules and the magnesium stearate of the prescription amount to obtain drug-containing layer granules;
(2) Preparing particles of a propulsion layer:
mixing povidone, sodium carboxymethylcellulose, hydroxypropyl cellulose, sodium chloride, red iron oxide, hydroxypropyl methylcellulose, 95% ethanol and purified water according to the prescription amount of the propulsion layer, granulating, drying, finishing, and then uniformly mixing the granules with the prescription amount of magnesium stearate to obtain propulsion layer granules;
(3) Double-layer tablet pressing:
pressing the drug-containing layer granules and the propelling layer granules by a double-layer tablet high-speed tablet press to obtain a double-layer tablet;
(4) Coating with a controlled release film:
uniformly mixing cellulose acetate, polyethylene glycol, purified water and acetone according to the prescription amount of the controlled release film coating liquid to obtain a controlled release film coating liquid, coating the double layers, and drying to obtain a controlled release film coating tablet;
(5) Laser drilling:
performing laser drilling on the controlled release film-coated tablet, and performing single drilling on one side of a drug layer of the tablet to obtain the drilled controlled release film-coated tablet;
(6) Curing, drying and coating a water-soluble film:
and (3) uniformly mixing the gastric-soluble film coating premix and purified water according to the prescription amount of the soluble film coating solution to obtain the soluble coating solution, coating the perforated controlled-release film coating tablet, and drying to obtain the glipizide controlled-release tablet.
7. The preparation method of glipizide controlled release tablets according to claim 6, characterized in that: in the step (3), the thickness ratio of the medicine-containing layer to the propelling layer is 2:1-3:2.
8. The preparation method of glipizide controlled release tablets according to claim 6, characterized in that: in the step (5), the aperture range is 0.5-1mm.
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