CN102988324A - Preparation for glipizide compression-coated controlled-release tablets - Google Patents
Preparation for glipizide compression-coated controlled-release tablets Download PDFInfo
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- CN102988324A CN102988324A CN2012104480371A CN201210448037A CN102988324A CN 102988324 A CN102988324 A CN 102988324A CN 2012104480371 A CN2012104480371 A CN 2012104480371A CN 201210448037 A CN201210448037 A CN 201210448037A CN 102988324 A CN102988324 A CN 102988324A
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Abstract
The invention provides a glipizide compression-coated controlled-release tablet preparation which is in the form of zero-order release for a long time, and the preparation is tablets prepared by a compression-coating technology. An indissolvable medicine, namely, glipizide, is solubilized by adopting an inclusion compound technology, and the integrated tablets are formed by pressing tablet cores and shell layers, wherein both of the tablet cores and the shell layers contain glipizide and gel-forming macromolecular substances, and disintegration-inhibiting substances capable of enhancing gel toughness are further contained in the shell layers. The glipizide compression-coated controlled-release tablets according to the invention can release medicines with a constant speed or an approximately constant speed in 24 hours in vitro and in vivo, has the characteristics of being low in cost, easy to realize mass production and the like compared with the conventional osmotic pump-type controlled-release tablet preparations on the market, and can provide a research basis and a production technology platform for the development of controlled-release preparations. The glipizide compression-coated controlled-release tablets only need to be taken once everyday, thus enhancing clinical compliance.
Description
Technical field
The present invention relates to a kind of glipizide pressed coated controlled release tablet, belong to field of pharmaceutical preparations, adopt clathrate technology and pressed coated technology to prepare Glipizide controlled release tablets, present steady and lasting release, take every day and once can keep effective glipizide blood drug level.
Background technology
Diabetes have become the third-largest disease of serious harm human health after cardiovascular and cerebrovascular vessel, malignant tumor.The chemical name of glipizide (glipizide) is 1-cyclohexyl-3-[p-(2-(5-methylpyrazine carbonyl amide) ethyl) phenyl sulfonyl] urea; a kind of lipotropy weak acid; the pKa value is 5.9; be second filial generation sulfonylurea oral antidiabetic drug; the blood glucose that reaches is on an empty stomach after the meal reduced, and glycolated hemoglobin (HbAlc) descends 1%～2%.Begin the beginning of the eighties for clinical, the glipizide oral absorption is quick and complete, and without first pass effect, the Main Function of this type of medicine is for stimulating the beta Cell of islet excreting insulin, and mechanism is the sulfonylureas receptor-specific combination on the β cell membrane, thereby makes the K+ pathway closure, cause that transmembrane potential changes Ca
2+Passage is opened, Ca in the cytosol
2+Raise, impel insulin secretion.Also have in addition the pancreas external effect, comprise the insulin-resistant states that improves peripheral tissues's (such as liver, muscle, fat).
The Half-life in vivo of conventional glipizide ordinary tablet is shorter, about 2～4h, and needs were taken two to three times in one day.Glipizide XL (Glucotrol
) be that Pfizer company is according to the osmotic pump type Glipizide controlled release tablets of special gastrointestinal therapeutic system (GITS) design, it has adopted the GITS/OROS patented technology (US 5024843, US 5091190, US 5545413, US 6361795) of Alza company, goes on the market in the U.S. in 1994.Compare with ordinary tablet, osmotic pump tablet in vivo and in vitro in the 24h with constant speed or near the constant release medicine, compare with other sustained-release preparations, its blood concentration fluctuation is minimum, untoward reaction is minimum.Administration number of times reduces simultaneously, and patient's compliance increases.Because drug release behavior is not subjected to the factor affecting such as media environment pH value, enzyme, gastrointestinal motility and food, the inside and outside dependency is good.This osmotic pumps label is comprised of two-layer, and one deck is for containing the glipizide medicine layer, and another layer is parmacodynamics-less activity but the push layer of tool osmotically active.This label skin comprises the semi-transparent rete of cellulose acetate, and this semipermeable membrane can not make medicine and adjuvant see through the clothing film, can not make that macromole enters in the clothing film in the liquid, and hydrone is seen through.
The controlled releasing penetrant pump processing step is many, technique is loaded down with trivial details, cost is higher, and uses organic solvent in its coating process, is unfavorable for large production.Japan Patent CN 1161200A has invented a kind of nifedipine pressed coated solid preparation of lasting release, it comprises the nuclear of the high molecular weight material that contains nifedipine and form hydrophilic gel and is used for the nuclear coating, contain nifedipine, form the high molecular weight material of hydrophilic gel and the shell of disintegrate inhibiting substances, said preparation is taken and once just can keep effective nifedipine plasma concentration and reach 24h or longer every day, it can provide and nifedipine (Pfizer clinically, the nifedipine osmotic pump preparation) identical clinical efficacy, and it is more insensitive to machinery concussion and stress state.Said preparation technique is simple, and preparation process is few, not with an organic solvent, greatly reduces large production cost, and the large manufacturing feasibility of alternative osmotic pump preparation is arranged.The present invention is according to this patented technology, the insoluble drug glipizide carried out the research of the pressed coated controlled release tablet behind the enclose solubilising, for insoluble drug provides technical foundation in the development of controlled release form.
Summary of the invention
The purpose of this invention is to provide a kind of glipizide pressed coated controlled release tablet, although it contains the label with slow releasing function, but take every day and can keep once effectively stably that the glipizide blood concentration reaches 24h or longer, and it is insensitive reducing to greatest extent food and machinery concussion to the impact of release on machinery concussion and stress state, thereby is expected to replace the application of osmotic pump preparation in large production.
The principal character of preparation of the present invention is by the pressed coated technology, realize the Zero order controlled releasing release, toughness by disintegrate inhibiting substances reinforcement gel layer in the shell reduces the impact of food and machinery concussion, and the release glipizide that the label of it slow release that possesses can be slower.
Medicine of the present invention adopts inclusion method that glipizide is carried out solubilising, and selecting beta-schardinger dextrin-is carrier, adopts the polishing preparation, and the mol ratio of described glipizide and cyclodextrin or derivatives thereof is 1: 1～20, and preferred 1: 2～10.
The pressed coated tablet that tablet of the present invention is comprised of the shell of the macromolecular material of a label and layer of gel character.
Label contains glipizide-Benexate Hydrochloride and can form the high molecular weight material of hydrophilic gel.The high molecular weight material that can form hydrophilic gel is dispersed in the label, swelling forms gel when contacting with water, the example comprises cellulose derivative such as hydroxypropyl cellulose (Hydroxyproylcellulose, HPC), hydroxypropyl emthylcellulose (Hydroxyproylmethylcellulose, HPMC), methylcellulose (Methylcellulose, MC), sodium carboxymethyl cellulose (Sodium carboxymethylcellulose, CMC-Na) etc.Wherein, cellulosic hydroxyl low-grade alkyl ether, hydroxypropyl cellulose (HPC) and hydroxypropyl emthylcellulose (HPMC) are preferred, particularly hydroxypropyl cellulose (HPC).HPC and HPMC all have multiple viscosity, and with regard to HPC, alternative is HPC-SL (3～5.9cp), HPC-L (6～10cp), ((1000～4000cp), its viscosity number is to measure in 20 ℃ 2% HPC aqueous solution to 150～400cp), HPC-H to HPC-M.Show according to documents and materials, use full-bodied gel rubber material can reduce the release rate of active component from whole preparation, and use low viscous gel rubber material can increase release rate, and therefore, the suitable speed of selecting and from label, discharging in conjunction with the gel rubber material scalable glipizide of different viscosities.The weight that label can contain the high molecular weight material that can form hydrophilic gel is 10～90%, preferred 15%～40%.
Label also can contain for example excipient (starch based: potato starch, dextrin except the high molecular weight material that contains hydrophilic gel; Saccharide: lactose, Sorbitol, glucose, sucrose), disintegrating agent (cross-linking sodium carboxymethyl cellulose, starch, low-substituted hydroxypropyl cellulose, crospolyvinylpyrrolidone), lubricant (magnesium stearate, Pulvis Talci, micropowder silica gel) etc.The preparation of label can be adopted powder vertical compression technique or wet granulation technology.
For prepared compression coated tablets being reached stablize lasting release, the final prescription that needs to regulate label forms, and makes glipizide from the dissolution rate that has a tablet of same composition with label be:
Behind the 45min 15～60%, preferred 20～55%
Behind the 2h at least 80%, preferred 85%.
Shell principal character of the present invention is except containing glipizide-Benexate Hydrochloride, form the polymer substance of hydrophilic gel, also having the disintegrate inhibiting substances.The disintegrate inhibiting substances is a kind of pharmaceutically useful, macromolecular material with pharmacology inertia, it can form the dependent gel-type vehicle of a kind of non-pH with the polymer substance that forms hydrophilic gel, the existence of disintegrate inhibiting substances has strengthened intensity and the toughness of shell, the aqueous passage length is lengthened, thereby slow down the speed of drug release, make simultaneously the impact of shell unable to take food thing or oscillating force, gradually stable corrosion release in digestive tract.The dependent insoluble polymer of this common right and wrong pH of class disintegrate inhibiting substances, they can be used as substrate or the release-controlled film of sustained-release preparation.Can preferably use be ethyl cellulose and
RS or RL PO.The contained disintegrate inhibiting substances of shell its to account for weight be 5～40%, preferred 10～20%.
The same label of classification of the selected formation hydrophilic gel of shell polymer substance.It is 30～80% that shell contains the polymer substance weight that can form hydrophilic gel, preferred 40～60%.
Shell also can contain for example excipient (starch based: potato starch, dextrin except containing glipizide-Benexate Hydrochloride, the polymer substance that forms hydrophilic gel, disintegrate inhibiting substances; Saccharide: lactose, Sorbitol, glucose, sucrose), disintegrating agent (cross-linking sodium carboxymethyl cellulose, starch, low-substituted hydroxypropyl cellulose, crospolyvinylpyrrolidone), lubricant (magnesium stearate, Pulvis Talci, micropowder silica gel) etc.The preparation of shell can be adopted powder vertical compression technique or wet granulation technology.
For prepared compression coated tablets being reached stablize lasting release, the final prescription that needs to regulate shell forms, and makes glipizide from the dissolution rate that has a tablet of same composition with label be:
Behind the 2h 10～60%, preferred 10～40%,
Behind the 4h 30～80%, preferred 20～60%,
Behind the 6h at least 75%, preferred 60%.
Compression coated tablets of the present invention is comprised of above-mentioned label and shell, and it can be first by powder vertical compression or wet granulation technology preparation, and the dried seed-coating machine of rear use (pressed coated machine) to label, finally makes glipizide pressed coated controlled release tablet with the shell coating.The ordinary circumstance lower sheeting does not have special condition restriction, and the suitable tabletting pressure of label is at 30～50N, and the tabletting pressure of whole compression coated tablets is at 90～100N.In 5～7mm scope, the diameter of compression coated tablets is usually in 9～12mm scope usually for the diameter of label.The glipizide pressed coated controlled release tablet of the present invention's preparation shows following dissolution characteristic:
Behind the 2h 2～30%, preferred 2.5～25%, more preferably 3～8%,
Behind the 4h 7～40%, preferred 10～30%, more preferably 11～20%,
Behind the 6h at least 65%, preferably at least 40%, more preferably at least 30%.Usually, pressed coated controlled release tablet of the present invention contains 1～40mg, preferred 5～20mg glipizide.The weight ratio of the content of glipizide in label and shell is 1/4～3/1, preferable range 1/3～2/1.That form with clathrate exists to mixing or being distributed to glipizide in the compression coated tablets of the present invention, crystalline material that also can glipizide, namely glipizide is through micronization, and particle size distribution is between 100 μ m～10nm.
Because pressed coated controlled release tablet of the present invention has said structure, when orally using, it assimilates liquid or moisture in upper gastro-intestinal tract, its shell forms first the dissolvable matrix of gel-type, but because the adding of disintegrate inhibitor, its gel mechanical strength is larger, under the facilitation of peristalsis of the digest tract, can not cave in fast, but from external stabilization and be transformed into slowly gel, continue thereby shell is stable from unilateral release glipizide clathrate, glipizide disengages from clathrate again.(8～10h), said preparation has arrived the lower digestive tract bottom of water content, and label begins slow release, presents zero level and stablizes lasting release thereby keep whole compression coated tablets when the drug release of shell substrate is complete.Therefore, tablet of the present invention can improve the gastral wriggling facilitation of antagonism, takes every day once and can keep effective blood drug level.
The implementation case
Embodiment 1
Label
With the even mix homogeneously of above-mentioned raw materials (except magnesium stearate), the rear 60 ℃ of dryings of granulating, and the granulate that sieves, rear adding magnesium stearate mix homogeneously.Under 30N pressure, use the single punch tablet machine tabletting, form the core sheet (diameter=7mm) of every heavy 94.5mg.Shell
With the even mix homogeneously of above-mentioned raw materials (except magnesium stearate), the rear 60 ℃ of dryings of granulating, and the granulate that sieves, rear adding magnesium stearate mix homogeneously.Dried seed-coating machine under 90N pressure (Kikusui Cleanpress Corret 18DC) tabletting makes the combination of shell and previously prepared label, forms the compression coated tablets that the contains glipizide 5mg (diameter=9mm) of every weight 400mg.
Label
With the even mix homogeneously of above-mentioned raw materials (except magnesium stearate), the rear 60 ℃ of dryings of granulating, and the granulate that sieves, rear adding magnesium stearate mix homogeneously.Under 30N pressure, use the single punch tablet machine tabletting, form the core sheet (diameter=7mm) of every heavy 112mg.
Shell
With the even mix homogeneously of above-mentioned raw materials (except magnesium stearate), the rear 60 ℃ of dryings of granulating, and the granulate that sieves, rear adding magnesium stearate mix homogeneously.Dried seed-coating machine under 90N pressure (Kikusui Cleanpress Corret 18DC) tabletting makes the combination of shell and previously prepared label, forms the compression coated tablets that the contains glipizide 5mg (diameter=9mm) of every weight 410mg.
Embodiment 3
Label
With the even mix homogeneously of above-mentioned raw materials (except magnesium stearate), the rear 60 ℃ of dryings of granulating, and the granulate that sieves, rear adding magnesium stearate mix homogeneously.Under 30N pressure, use the single punch tablet machine tabletting, form the core sheet (diameter=7mm) of every heavy 187mg.
Shell
With the even mix homogeneously of above-mentioned raw materials (except magnesium stearate), the rear 60 ℃ of dryings of granulating, and the granulate that sieves, rear adding magnesium stearate mix homogeneously.Dried seed-coating machine under 90N pressure (Kikusui Cleanpress Corret 18DC) tabletting makes the combination of shell and previously prepared label, forms the compression coated tablets that the contains glipizide 5mg (diameter=9mm) of every weight 480mg.
Test example 1
Adopt binary cycle two preparation trial design.Get 3 of healthy rabbits, body weight 2.0～2.5kg is as animal subject.Fasting 12h before the administration.Give respectively the pressed coated tablet of the oral commercially available osmotic pump preparation of rabbit (Glipizide XL) and case study on implementation 1 preparation, dosage is 0.275mg/kg.After administration the 0.5th, 1.0,2,4,6,8,10,12,14,24,36h gets blood, and each 1ml puts many husbands' pipes that heparin is processed, and the centrifugal 10min of 4000rpm gets upper plasma, puts-20 ℃ of environment and places, and is stand-by.Through the clean after date in 1 week, intersect respectively oral another preparation, and press same method and process, relatively blood drug level and the bioavailability of glipizide.Result such as following table 1.
Pharmacokinetic parameters in table 1 embodiment 1 and the Glipizide XL preparation body
Taking the compression coated tablets of embodiment 1 compares with commercially available Glipizide XL osmotic pump preparation, blood concentration area under curve AUC is more or less the same, embodiment 1 is lower than commercially available AUC, carry out the calculating of bioavailability, glipizide pressed coated controlled release tablet average relative bioavailability is (87.66 ± 1.56) %, in 80～120% scopes, carries out the t check, finally show both bioequivalences, embodiment 1 can keep the curative effect of 24h.
Test example 2
According to 2010 editions drug release determination methods of Chinese Pharmacopoeia (appendix XD first method), adopt the device of dissolution method (appendix XC first method), take pH 7.4 phosphate buffer 500ml as solvent, temperature is 37 ± 1 ℃, rotating speed is 100r/min, and this method operation is 0,1,2,4,6,8,10,12,16,24h gets respectively solution 10ml, filter with 0.45 μ m microporous filter membrane, get subsequent filtrate, and immediately in process container, replenish pH 7.4 phosphate buffer 1 0ml.Sample introduction 20 μ l, the record chromatographic peak area is tried to achieve the burst size of time point by measurement result substitution standard curve, namely gets total release percentage after calibrated.The medicine total release percentage is calculated as follows:
C wherein
iBe drug level (μ gml
-1); V
0Be release medium volume (ml); V
MendBe fluid infusion volume (ml); W is example weight (mg); F is the percentage composition (%) of preparation of Chinese medicine.
In Vitro Dissolution the results are shown in Table 2.
The cumulated release amount (%) of table 2 glipizide from tablet
Description of drawings
Fig. 1 is embodiment 1～3 In Vitro Dissolution curve.
Fig. 2 be embodiment 1 with commercially available osmotic pump tablet (Glipizide XL) body in blood drug level through the time curve.
Claims (7)
1. a glipizide Benexate Hydrochloride is characterized in that adopting the polishing preparation of inclusion complex, and the mol ratio of described glipizide and cyclodextrin or derivatives thereof is 1: 1～20.
2. pressed coated tablet that contains glipizide Benexate Hydrochloride claimed in claim 1, it comprise the label of the high molecular weight material that contains the glipizide Benexate Hydrochloride and form hydrophilic gel and be used for to the nuclear coating, contain glipizide Benexate Hydrochloride, the high molecular weight material that forms hydrophilic gel and the shell of disintegrate inhibiting substances, it is characterized in that the dissolution rate of glipizide from the pressed coated tablet is (first method according to the dissolution test method of 2010 editions regulations of Chinese Pharmacopoeia carries out dissolution test):
Behind the 2h 10%～30%
Behind the 4h 40%～60%
Behind the 6h at least 50%.
3. in the tablet as claimed in claim 2, glipizide from the dissolution rate that has a tablet of same composition with label is:
Behind the 45min 15%～60%
Behind the 2h at least 80%.
4. in the tablet as claimed in claim 2, wherein glipizide from the dissolution rate that has a tablet of same composition with shell is:
Behind the 2h 20%～60%
Behind the 4h 30%～80%
Behind the 6h at least 75%.
5. such as each tablet in the claim 2～4, wherein label contains the high molecular weight material of the formation hydrophilic gel of 10～80% weight, and outer shell contains the high molecular weight material of formation hydrophilic gel of 40～90% weight and the disintegrate inhibiting substances of 10～40% weight.
6. as in each the tablet of claim 2～5, wherein disintegrate inhibiting substances is ethyl cellulose, polyethyl acrylate, polymethyl methacrylate and/or ethyl cellulose.
7. such as the tablet of claim 2～6 in each, the high molecular weight material that wherein forms hydrophilic gel is the hydroxyl low-grade alkyl ether of cellulose family, such as hydroxypropyl cellulose, hydroxypropyl emthylcellulose.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106420649A (en) * | 2016-11-21 | 2017-02-22 | 中国药科大学 | Acetaminophen press-coated controlled release tablet based on polyelectrolyte self-assembled film and preparation method of acetaminophen press-coated controlled release tablet |
| CN108379234A (en) * | 2018-04-19 | 2018-08-10 | 广东药科大学 | A kind of Glipizide composition and preparation method thereof based on microenvironment pH regulation and control |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1161200A (en) * | 1995-11-28 | 1997-10-08 | 拜尔公司 | Long-lasting release nifedipine prepn. |
| CN1600801A (en) * | 2003-09-26 | 2005-03-30 | 清华大学 | Preparation method of clathrate of glipizide cyclodextrin |
-
2012
- 2012-11-12 CN CN2012104480371A patent/CN102988324A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1161200A (en) * | 1995-11-28 | 1997-10-08 | 拜尔公司 | Long-lasting release nifedipine prepn. |
| CN1600801A (en) * | 2003-09-26 | 2005-03-30 | 清华大学 | Preparation method of clathrate of glipizide cyclodextrin |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106420649A (en) * | 2016-11-21 | 2017-02-22 | 中国药科大学 | Acetaminophen press-coated controlled release tablet based on polyelectrolyte self-assembled film and preparation method of acetaminophen press-coated controlled release tablet |
| CN108379234A (en) * | 2018-04-19 | 2018-08-10 | 广东药科大学 | A kind of Glipizide composition and preparation method thereof based on microenvironment pH regulation and control |
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Application publication date: 20130327 |