CN105687161A - Tacrolimus slow-release mini-pill and preparation method thereof - Google Patents

Abstract

A tacrolimus slow-release mini-pill and a preparation method thereof are disclosed, the tacrolimus slow-release mini-pill includes a drug-containing mini-pill and a coating layer, the drug-containing mini-pill is coated with the coating layer, the drug-containing mini-pill comprises 5mg of tacrolimus, 70mg of a blank pill core, 120-220mg of a filler, 25-125mg of a lubricant and 5-50mg of a binder, the coating layer comprises 35-175mg of Eudragit NE30D and 5-52mg of talc powder, preparation steps of the preparation method are as follows: 1, preparing materials; 2, mixing; 3, preparing the binder; 4, pelleting; 5, preparing a coating agent; 6, coating; 7, filling; and 8, aluminum molding and finishing. The tacrolimus slow-release mini-pill is used for preventing of graft rejection reaction after liver or kidney transplantation and treatment of graft rejection reaction which cannot be controlled by other immunosuppressive drugs after liver or kidney transplantation, and the tacrolimus slow-release mini-pill is more secure, better in stability, and smaller in adverse reactions.

Description

A kind of tacrolimus slow release micropill and preparation method thereof

Technical field

The invention belongs to chemical medicine slow releasing preparation technical field, be specifically related to a kind of tacrolimus slow release micropill and preparation method thereof。

Background technology

When allohisto compatibility, organ transplantation, graft is often produced rejection (transplantrejection) by the immune system of receptor, this is a sufficiently complex immunological phenomenon, relate to cell and antibody-mediated panimmunity damage mechanisms, the reaction of human major histocompatibility antigen HLA (humanleucocyteantigen) being both in graft, donor determines the light of rejection or weight with the difference degree of receptor HLA。Graft-rejection is different with pathological change by pathogenesis, hyperacute rejection can be divided into, acute rejection and chronic rejection, graft was occurred rapid and violent rejection to be called hyperacute rejection to 24 hours by receptor several minutes after the transfer, a couple of days after the transfer can be there is in acute rejection, also, after can betiding the several months, chronic rejection can occur within the several years。

According to metamorphosis and the pathogenesis of rejection, it is divided into hyperacute rejection, acute rejection and chronic rejection。

1, hyperacute rejection

A few minutes or several hours after the transfer occur, and there is donor specific HCA antibody existence existing with receptor in it, or the abo blood group of donor and receptor is not inconsistent relevant。Transplant organ is changed into rapidly kermesinus, and with hemorrhagic necrosis, in graniphyric, volume enlargement, quality is soft, and histological examination polyangitis widely accompanies thrombosis, blood vessel wall fibrinoid necrosis and neutrophil infiltration, and has IgG, IgM and complement to exist。

2, acute rejection

More typically, during without immunosuppressant therapy, can occur within a couple of days, when immunosuppressant therapy, can occur after several months even several years, cellular type rejection and vascular type rejection can be divided into。

Cellular type rejection: show as in transplant organ, big amount lymphocyte, monocyte infiltration, lymph mostly is CD4+ or CD8+T cell。Cell acute kidney transplantation exclusion reaction。

Vascular type rejection: main manifestations is the necrotizing vasculitis of tiny tremulous pulse。The necrotizing vasculitis of tiny tremulous pulse。

3, chronic rejection

Being often repeatedly the accumulation of acute rejection, prominent pathological changes is tunica intima fibrosis, with parenchyma atrophy and the interstitial fibrosis chronic inflammation cellular infiltration of transplant organ。

Currently there are and prevent liver or the postoperative transplant rejection of renal transplantation, treatment liver or the uncontrollable transplant rejection tacrolimus capsules of renal transplantation other immunosuppressive drugs of postoperative application, but the medicine stability of this capsule is not fine, and untoward reaction is difficult to determine, the untoward reaction that most of patients occurs after surgery in several weeks is more。

Summary of the invention

It is an object of the invention to provide and a kind of prevent liver or the postoperative transplant rejection of renal transplantation, tacrolimus slow release micropill for the treatment of liver or the renal transplantation postoperative application uncontrollable transplant rejection of other immunosuppressive drugs and preparation method thereof, its safety is higher, stability better, and untoward reaction is less。

The purpose of the present invention is achieved through the following technical solutions: a kind of tacrolimus slow release micropill, including pastille micropill, coatings, pastille micropill is wrapped up by described coatings, described pastille micropill includes: 5mg tacrolimus, 70mg celphere, 120-220mg filler, 25-125mg lubricant, 5-50mg binding agent, and described coatings includes: 35-175mg is strange NE30D, 5-52mg Pulvis Talci especially。

The best in quality proportioning of described pastille micropill Raw is: 5mg tacrolimus, 70mg celphere, 200mg filler, 55mg lubricant, 10mg binding agent。

The best in quality proportioning of described coatings Raw is: 95mg is strange NE30D, 21mg Pulvis Talci especially。

Described filler is microcrystalline Cellulose。

Described lubricant is Pulvis Talci。

Described binding agent is hypromellose。

Described coatings also includes sodium lauryl sulphate or Polyethylene Glycol trace。

The preparation method of described a kind of tacrolimus slow release micropill, comprises following operation:

Step 1: get the raw materials ready: by above-mentioned quality proportioning, use pulverizer to pulverize tacrolimus, crosses 100 mesh sieves；

Step 2: mixing: weigh tacrolimus according to above-mentioned quality proportioning, microcrystalline Cellulose is put in three-dimensional mixer and mixed 30 minutes, makes fine drug powder, takes out standby；

Step 3: the preparation of binding agent: weigh appropriate hypromellose by above-mentioned quality proportioning, adds appropriate hot water and is configured to the binding agent that concentration is 2%, standby；

Step 4: pill: mixed fine drug powder is put in the charging spout of centrifugal pellet processing machine, binding agent is put in feed tank, and celphere is put in pot, opens machine, adjust parameter, start hydrojet, start when capsule core has damp for powder, after fine drug powder has all spread, charging spout adds Pulvis Talci, continue for powder, after Pulvis Talci has all spread, discharging；Then using vulcanization bed drying machine to dry, first dry with cool breeze, after epidermis parches, open Hot-blast Heating, inlet temperature, at 50-55 degree Celsius, uses 14,24 mesh sieve after drying, the pastille micropill taking 14-24 order size is standby；

Step 5: the preparation of coating materials: weigh especially strange NE30D, Pulvis Talci, sodium lauryl sulphate, purified water by above-mentioned quality proportioning, first sodium lauryl sulphate is joined and purified water stirs evenly dissolving, add after especially strange NE30D stirs evenly, limit stirring just adds Pulvis Talci, standby after stirring 10 minutes；

Step 6: coating: by the pastille micropill of 14-24 order size, put in fluidized-bed coating machine, coating materials is put in feed tank, stir constantly, open machine, adjust parameter, start coating, to be coated dose be finished after, start to warm up maintenance temperature of charge more than 40 degree, dry 30 minutes, cooling, discharging, closing machine；

Step 7: fill: the pastille micropill after above-mentioned coating is used capsule filling machine, loads pastille micropill in 0# capsule；

Step 8: plastic-aluminum: above-mentioned capsule is used aluminium-plastic bubble plate packing machine, is packaged into aluminium-plastic panel, packed products。

Beneficial effects of the present invention: the invention provides and a kind of prevent liver or the postoperative transplant rejection of renal transplantation, tacrolimus slow release micropill for the treatment of liver or the renal transplantation postoperative application uncontrollable transplant rejection of other immunosuppressive drugs and preparation method thereof, its safety is higher, stability is better, and untoward reaction is less, adopt the slow releasing preparation of novelty and the technology that pellet preparations is two kinds advanced, slow release refers to by delaying medicine rate of releasing drug from this dosage form, reduce medicine and enter the absorption rate of body, thus playing more stable therapeutic effect；Micropill has medicine and increases at gastrointestinal tract surface distributed area, can reduce zest, improves bioavailability, is not affected by gastric emptying factor simultaneously, and drug absorption in vivo is uniform, and individual variation is little；The advantages such as technology two kinds advanced applies the technical advantage more enhancing this medicine simultaneously, compared with oral liquid, has medicine stability good, packaging, transport, and storage is convenient, its preparation method is simple, it is adaptable to commercial production。

At molecular level, the effect of tacrolimus is clearly and utilizes it to combine with cellular proteins (FKBP12), and produces effectiveness at intracellular accumulation。FKBP12-tacrolimus complex can combine in specific manner and suppress calcinurin, and it can suppress produced calcium ion dependent form message conducting path effect in T cell, therefore prevents transcribing of discontinuity lymphokine genes。This medicine is to have the medicine that hyperimmunization suppresses, and its activity in vitro and all has been found in experiment in vivo。This medicine suppresses to be formed the lymphocytic generation of cytotoxicity of main transplant rejection effect。This medicine suppresses the activation of T cell and the proliferative effect of t helper cell dependent form B cell, also can suppress the expression of the generation such as lymphokines such as interleukin-2, interleukin-3 and gamma interferons and Interleukin 2 Receptor。At molecular level, the effect of this medicine is seemingly produced by being attached to cellular proteins (FKBP), and this protein will also result in this compound cumulative at iuntercellular。Finding in test in vivo, this medicine demonstrates liver and renal transplantation effective。

Detailed description of the invention

Embodiment 1

A kind of tacrolimus slow release micropill, including pastille micropill, coatings, pastille micropill is wrapped up by described coatings, described pastille micropill includes: 5mg tacrolimus, 70mg celphere, 120-220mg filler, 25-125mg lubricant, 5-50mg binding agent, and described coatings includes: 35-175mg is strange NE30D, 5-52mg Pulvis Talci especially。

The best in quality proportioning of described pastille micropill Raw is: 5mg tacrolimus, 70mg celphere, 200mg filler, 55mg lubricant, 10mg binding agent。

The best in quality proportioning of described coatings Raw is: 95mg is strange NE30D, 21mg Pulvis Talci especially。

Described filler is microcrystalline Cellulose。

Described lubricant is Pulvis Talci。

Described binding agent is hypromellose。

Described coatings also includes sodium lauryl sulphate or Polyethylene Glycol trace。

Embodiment 2

The preparation method of a kind of tacrolimus slow release micropill, comprises following operation:

Step 1: get the raw materials ready: by above-mentioned quality proportioning, use pulverizer to pulverize tacrolimus, crosses 100 mesh sieves；

Step 2: mixing: weigh tacrolimus according to above-mentioned quality proportioning, microcrystalline Cellulose is put in three-dimensional mixer and mixed 30 minutes, makes fine drug powder, takes out standby；

Step 3: the preparation of binding agent: weigh appropriate hypromellose by above-mentioned quality proportioning, adds appropriate hot water and is configured to the binding agent that concentration is 2%, standby；

Step 4: pill: mixed fine drug powder is put in the charging spout of centrifugal pellet processing machine, binding agent is put in feed tank, and celphere is put in pot, opens machine, adjust parameter, start hydrojet, start when capsule core has damp for powder, after fine drug powder has all spread, charging spout adds Pulvis Talci, continue for powder, after Pulvis Talci has all spread, discharging；Then using vulcanization bed drying machine to dry, first dry with cool breeze, after epidermis parches, open Hot-blast Heating, inlet temperature, at 50-55 degree Celsius, uses 14,24 mesh sieve after drying, the pastille micropill taking 14-24 order size is standby；

Step 5: the preparation of coating materials: weigh especially strange NE30D, Pulvis Talci, sodium lauryl sulphate, purified water by above-mentioned quality proportioning, first sodium lauryl sulphate is joined and purified water stirs evenly dissolving, add after especially strange NE30D stirs evenly, limit stirring just adds Pulvis Talci, standby after stirring 10 minutes；

Step 6: coating: by the pastille micropill of 14-24 order size, put in fluidized-bed coating machine, coating materials is put in feed tank, stir constantly, open machine, adjust parameter, start coating, to be coated dose be finished after, start to warm up maintenance temperature of charge more than 40 degree, dry 30 minutes, cooling, discharging, closing machine；

Step 7: fill: the pastille micropill after above-mentioned coating is used capsule filling machine, loads pastille micropill in 0# capsule；

Step 8: plastic-aluminum: above-mentioned capsule is used aluminium-plastic bubble plate packing machine, is packaged into aluminium-plastic panel, packed products。

Embodiment 3

Tacrolimus is through liver CYP3A4 enzymes metabolism。Also evidence suggests and carry out gastrointestinal metabolic by the CYP3A4 enzyme in intestinal wall。It is known to suppress or induce the medicine of CYP3A4 enzyme or medical herbs to share the metabolism being likely to affect tacrolimus with other, thus increasing or reduce the blood concentration of tacrolimus。Therefore, if during with the drug combination that potential can change CYP3A4 enzymes metabolism, it is recommended that the blood drug level of monitoring tacrolimus, the dosage of tacrolimus is adjusted to maintain similar tacrolimus exposed amount。

Show that following medicine can increase tacrolimus blood drug level clinically:

Stronger interaction is there is with antifungal drug such as ketoconazole, fluconazol, itraconazole and voriconazole, Macrolide erythromycin or hiv protease inhibitor (such as ritonavir)。During with these drug combinations, almost all of patient is required for reducing the dosage of tacrolimus。

More weak interaction is there is with clotrimazole, clarithromycin, josamycin, nifedipine, nicardipine, diltiazem, verapamil, danazol, ethinylestradiol, omeprazole and nefazodone。

Experiment in vitro shows that following medicine is the potential inhibitor of tacrolimus metabolism: bromocriptine, cortisone, dapsone, Ergotamine, gestodene, lignocaine, mephenytoin, miconazole, midazolam, nilvadipine, norethindrone, chinidine, tamoxifen, triacetyloleandomycin。

Grapefruit juice can increase tacrolimus blood drug level, should avoid taking simultaneously。

The tacrolimus metabolism that lansoprazole and the ciclosporin potential suppression of energy are mediated by CYP3A4 so that it is full blood concentration raises。

Claims (8)

1. a tacrolimus slow release micropill, including pastille micropill, coatings, it is characterized in that: pastille micropill is wrapped up by described coatings, described pastille micropill includes: 5mg tacrolimus, 70mg celphere, 120-220mg filler, 25-125mg lubricant, 5-50mg binding agent, and described coatings includes: 35-175mg is strange NE30D, 5-52mg Pulvis Talci especially。

2. a kind of tacrolimus slow release micropill according to claim 1, it is characterised in that: the best in quality proportioning of described pastille micropill Raw is: 5mg tacrolimus, 70mg celphere, 200mg filler, 55mg lubricant, 10mg binding agent。

3. a kind of tacrolimus slow release micropill according to claim 1, it is characterised in that: the best in quality proportioning of described coatings Raw is: 95mg is strange NE30D, 21mg Pulvis Talci especially。

4. a kind of tacrolimus slow release micropill according to claim 1, it is characterised in that: described filler is microcrystalline Cellulose。

5. a kind of tacrolimus slow release micropill according to claim 1, it is characterised in that: described lubricant is Pulvis Talci。

6. a kind of tacrolimus slow release micropill according to claim 1, it is characterised in that: described binding agent is hypromellose。

7. a kind of tacrolimus slow release micropill according to claim 1, it is characterised in that: described coatings also includes sodium lauryl sulphate or Polyethylene Glycol trace。

8. the preparation method of a kind of tacrolimus slow release micropill according to claim 1-3, it is characterised in that: comprise following operation:

Step 1: get the raw materials ready: by above-mentioned quality proportioning, use pulverizer to pulverize tacrolimus, crosses 100 mesh sieves；

Step 2: mixing: weigh tacrolimus according to above-mentioned quality proportioning, microcrystalline Cellulose is put in three-dimensional mixer and mixed 30 minutes, makes fine drug powder, takes out standby；

Step 3: the preparation of binding agent: weigh appropriate hypromellose by above-mentioned quality proportioning, adds appropriate hot water and is configured to the binding agent that concentration is 2%, standby；

Step 4: pill: mixed fine drug powder is put in the charging spout of centrifugal pellet processing machine, binding agent is put in feed tank, and celphere is put in pot, opens machine, adjust parameter, start hydrojet, start when capsule core has damp for powder, after fine drug powder has all spread, charging spout adds Pulvis Talci, continue for powder, after Pulvis Talci has all spread, discharging；Then using vulcanization bed drying machine to dry, first dry with cool breeze, after epidermis parches, open Hot-blast Heating, inlet temperature, at 50-55 degree Celsius, uses 14,24 mesh sieve after drying, the pastille micropill taking 14-24 order size is standby；

Step 5: the preparation of coating materials: weigh especially strange NE30D, Pulvis Talci, sodium lauryl sulphate, purified water by above-mentioned quality proportioning, first sodium lauryl sulphate is joined and purified water stirs evenly dissolving, add after especially strange NE30D stirs evenly, limit stirring just adds Pulvis Talci, standby after stirring 10 minutes；

Step 6: coating: by the pastille micropill of 14-24 order size, put in fluidized-bed coating machine, coating materials is put in feed tank, stir constantly, open machine, adjust parameter, start coating, to be coated dose be finished after, start to warm up maintenance temperature of charge more than 40 degree, dry 30 minutes, cooling, discharging, closing machine；

Step 7: fill: the pastille micropill after above-mentioned coating is used capsule filling machine, loads pastille micropill in 0# capsule；

Step 8: plastic-aluminum: above-mentioned capsule is used aluminium-plastic bubble plate packing machine, is packaged into aluminium-plastic panel, packed products。