CN105534943B - Tacrolimus quick-release preparation and preparation method thereof - Google Patents
Tacrolimus quick-release preparation and preparation method thereof Download PDFInfo
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- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
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Abstract
The invention belongs to the technical field of pharmaceutical preparations and in particular relates to a Tacrolimus quick-release preparation and a preparation method thereof. The Tacrolimus quick-release preparation contains the following raw materials in parts by weight: 0.5 to 1.5 parts of Tacrolimus micropowder, 50 to 60 parts of bulking agent, 4 to 8 parts of binder, 1 to 4 parts of disintegrant and 0.5 to 2 parts of lubricant. The Tacrolimus quick-release preparation provided by the invention can meet the requirements of active components on dissolution and content uniformity, and the preparation method is simplified.
Description
Technical field
The invention belongs to pharmaceutical preparations technology field, and in particular to a kind of tacrolimuss quick releasing formulation and preparation method thereof.
Background technology
Tacrolimuss (Tacrolimus) are a kind of tunnings isolated from streptomyces, are a kind of macrolide
Class antibiotic, chemistry is entitled：
[3S-[3R*[E(1S*,3S*,4S*)],4S*,5R*,8S*,9E,12R*,14R*,15S*,16R*,18S*,19S*,
26aR*]] hexahydro -5,19- dihydroxy -3- of -5,6,8,11,12,13,14,15,16,17,18,19,24,25,26,26a- ten
[2- (4- hydroxy-3-methoxy cyclohexyls) -1- methyl ethylenes] -14,16- dimethoxy-4 's, 10,12,18- tetramethyl -8-
(2- acrylic) -15,19- epoxy -3H- pyridos [2,1-c] [1,4] oxazepine rings tricosane -1,7,20,21 (4H,
23H)-tetrone monohydrate, chemical constitution is shown in formula I：
Tacrolimuss are a kind of new potent immunosuppressant inhibitor, main by suppressing IL-2, IL-3, the release of IFN-γ
To suppress the expression of IL-2R, T lymphocytes are suppressed comprehensively, its immunosuppressant is stronger than ciclosporin 100 times.In recent years, tacrolimuss
As the first-line drug of anti-rejection after liver and kidney transplantation operation, while in treatment atopic dermatitiss, systemic erythema
Also positive effect is played in the autoimmune diseasees such as lupus, Autoimmune ophthalmopathy.
Tacrolimuss were researched and developed by Japanese Teng Ze Pharmaceutical Co., Ltd (being now Astellas Pharma Inc) in 1984
Listing, be mainly used in preventing liver or the postoperative transplant rejection of renal transplantation and treatment liver or renal transplantation is postoperative should
With the uncontrollable transplant rejection of other immunosuppressive drugs.In multiple country's listings.Tacrolimuss are in pH1.2
Dissolubility in the aqueous solution of～pH7.4 is relatively low, and dissolubility is without pH dependencies, but its permeability is higher, belongs to low molten
Solution high osmosis medicine, according to BCS classification II classes are belonged to.
Tacrolimuss belong to low dissolving high osmosis medicine, and absorbtivity in vivo is affected by the burst size of pharmaceutical preparation,
Its burst size but affected by the dissolubility of medicine, therefore improve tacrolimuss dissolubility, be tacrolimuss related preparations needs
The primary technical problem for solving.
The Tacrolimus Capsules (trade name Prograf) of Astellas Pharma Inc's production at present, and patent
Pharmaceutical composition of tacrolimus disclosed in CN129111C, CN101098875A, CN100515413C, CN1919816A etc. and its
Preparation method, prepares tacrolimuss quick releasing formulation using solid dispersion method.Particular content is：Using solvent method, fusion method
Tacrolimuss are made into solid dispersion etc. method, then it is size-reduced, mill or granulate after obtain the granule containing tacrolimuss or powder
End, loads capsule or tabletted after finally mixing granule or powder with other appropriate amount of auxiliary materials, be prepared into tacrolimuss speed
Release formulation.Although above-mentioned technology can improve the dissolution rate of tacrolimuss, its solid dispersion particles or powder are auxiliary with other
Material mixing when, because the particle diameter distribution between solid dispersion particles or powder and other adjuvants it is variant, in there is mixed process
The risk that content uniformity is difficult to ensure that.Meanwhile, operate relatively complicated, production cost higher using solid dispersion technology.Therefore,
It is necessary to research and develop a kind of dissolution for being remarkably improved tacrolimuss, and the simple tacrolimuss rapid release system of formula, preparation method
Agent.
Quick releasing formulation of the present invention refers to oral solid formulation of the dissolution in 60min more than 80%.
The content of the invention
In order to overcome the deficiencies in the prior art, the invention provides a kind of tacrolimuss quick releasing formulation, it can expire completely
The foot dissolution specification of tacrolimus oral administration solid preparation (specification 0.5mg～5mg), and its formula and preparation method are simple,
Solve prior art and there are problems that cumbersome and content.
To achieve these goals, technical scheme is as follows：
A kind of tacrolimuss quick releasing formulation, including the raw material of following weight portion meter：0.5～1.5 part of tacrolimuss micropowder, fill out
Fill 0.5～2 part of 50～60 parts of agent, 4～8 parts of binding agent, 1～4 part of disintegrating agent and lubricant.
Further, the tacrolimuss quick releasing formulation includes the raw material of following weight portion meter：1 part of tacrolimuss micropowder,
1 part of 55 parts of filler, 6 parts of binding agent, 2 parts of disintegrating agent and lubricant.
Further, particle diameter distribution D of the tacrolimuss micropowder90For 3～8 μm.
Further, the filler is the compositionss of Polyethylene Glycol and Mannitol, the Polyethylene Glycol and Mannitol
Weight ratio be (0.5～1.0):1.Preferably, the weight ratio of the Polyethylene Glycol and Mannitol is 0.8:1.
Further, the disintegrating agent is polydextrose and the compositionss of L- hydroxypropyl celluloses, the polydextrose
It is 1 with the weight ratio of L- hydroxypropyl celluloses:(0.25～0.45).Preferably, the polydextrose and L- hydroxypropyl celluloses
Weight ratio be 1:0.35.
Further, described adhesive is hypromellose and the compositionss of sodium carboxymethyl cellulose, the hydroxypropyl
The weight ratio of methylcellulose and sodium carboxymethyl cellulose is (0.2～0.6):1.Preferably, the hypromellose and carboxylic first
The weight ratio of base sodium cellulosate is 0.4:1.
Further, the lubricant is magnesium stearate.
Present invention also offers the preparation method of above-mentioned tacrolimuss quick releasing formulation, it is characterised in that comprise the following steps：
S1, control super micron mill admission pressure be 0.4～0.7Mpa, crushings pressure be 0.5～0.8Mpa, by he gram
Department is not added in super micron mill, and it is 3g～5g/ minutes to control feed rate, and to tacrolimuss micronizing is carried out, and is adopted
MALVERN2000 type laser particle size analyzers are measured to particle diameter distribution, control particle diameter distribution D90For 3～8 μm, him is obtained gram
Micropowder is not taken charge of, it is standby；
S2, by filler, disintegrating agent, the broken mesh sieve of mistake 100 of binding agent, it is standby；
S3, using efficient wet mixer-granulator by the tacrolimuss micropowder and the filler, disintegrating agent and bonding
Agent mixes, and is subsequently adding ethanol soft material, is pelletized using 24～30 mesh sieves, obtains wet granular；
S4, the wet granular is carried out into drying under reduced pressure at 40 DEG C～50 DEG C, using fast tester for water content at 100 DEG C
Loss on drying control, then with 24～30 mesh sieve granulate, obtains dry particl less than 1.5%；
S5, by the dry particl and mix lubricant it is uniform after be filled in capsule shells, obtain final product tacrolimuss quick releasing formulation.
Inventor has found during to the distribution of tacrolimuss raw material particle size and prescription composition research, when particle diameter distribution control
In D90More than 10 μm or D90During less than 3 μm, its dissolution is low.Draw through tests study analysis, tacrolimuss are indissoluble
Property the medicine, (D when diameter of aspirin particle increases90More than 10 μm), surface area reduces, and is unfavorable for medicine dissolution, causes dissolution to decline；
And tacrolimuss raw material particle size distribution it is excessively tiny when (D90Less than 3 μm), although in theory particle diameter reduces and is beneficial to medicine dissolution, but
Because raw material particle size it is too small, the weight saving of drug microparticles, cause drug microparticles from preparation disintegrate dispersion after rapid flotation in molten
Go out dielectric surface, while tacrolimuss raw material hydrophobicity is strong so as to drug microparticles cannot moistening, cause its dissolution to reduce.Enter
One step research finds, even if by tacrolimuss grain size of micropowder distributed controll in D90For 3～8 μm, if using single conventional constituents
Filler and binding agent prepare sample, the In Vitro Dissolution behavior of its sample does not still reach requirement and (grinds commercially available product difference with original
It is larger).
Further, by studying in a large number deeply and carefully, inventor surprisingly has found：After tacrolimuss micronized,
Control particle diameter distribution D90For 3～8 μm, while adopting specific prescription composition (with a certain proportion of Polyethylene Glycol and Mannitol
Compositionss as filler, using the compositionss of a certain proportion of polydextrose and L- hydroxypropyl celluloses as disintegrating agent, with one
The hypromellose of certainty ratio and the compositionss of sodium carboxymethyl cellulose as binding agent, using magnesium stearate as lubricant)
Made by quick releasing formulation and original grind commercially available product In Vitro Dissolution behavior congruence preferably (similar factors are more than 60), and product release is equal
One property is preferable, steady quality.Compared with prior art, operation simpler, production cost is reduced.
Polydextrose (CAS 68424-04-4) of the present invention is white or off-white powder granule.Polydextrose is
Water soluble dietary fiber, is a kind of food component with heath-function, and the aqueous soluble dietary that can supplement needed by human body is fine
Dimension, it can be used as thickening agent, filler and formula agent in food additive.Polydextrose has good water absorption and expansion
Property, inventor is surprised to find that it as the disintegrating agent in preparation, and can be compounded as disintegrating agent with L- hydroxypropyl celluloses
When disintegrate effect it is even more ideal.
Therefore, compared with prior art, advantage of the invention is that：
Tacrolimuss are carried out micronizing by the present invention using super micron mill, control particle diameter distribution D of Ke Mosi90For 3
～8 μm, make its dissolution after quick releasing formulation in conjunction with composition of raw materials of the present invention and significantly improve, tacrolimuss can be met completely
The dissolution specification of oral solid formulation；Simultaneously its formula is simple, it is not necessary to extra addition surfactant or solubilizing agent, hydrotropy
Agent, it is not necessary to be fabricated to solid dispersion, during tacrolimuss quick releasing formulation is prepared, directly adopts particle diameter distribution D90For 3
～8 μm of tacrolimuss raw material mixes with other adjuvants, prepares product using conventional wet granulation technology and is obtained and original
The consistent product of commercially available product In-vitro release curves is ground, and product dissolution homogeneity is preferably, steady quality, compared with prior art,
Operation is simpler, and production cost is lower, is conducive to industrialized production, with good application prospect.
Specific embodiment
Below in conjunction with embodiment, the invention will be further described, can make professional and technical personnel in the field more fully
Understand the present invention, but limit the scope of the present invention never in any form.
Embodiment 1
Formula：
| Raw material | Effect | Consumption |
| Tacrolimuss micropowder (D90=5 μm) | Main constituent | 1g |
| Polyethylene Glycol:Mannitol=0.8:1 (weight ratio) | Filler | 55g |
| Polydextrose:L- hydroxypropyl cellulose=1:0.35 (weight ratio) | Disintegrating agent | 6g |
| Hypromellose:Sodium carboxymethyl cellulose=0.4:1 (weight ratio) | Binding agent | 2g |
| Magnesium stearate | Lubricant | 1g |
Preparation method：
S1, control super micron mill admission pressure be 0.6Mpa, crushings pressure be 0.7Mpa, by tacrolimuss plus the excess of imports
In atomizer, it is 4g/ minutes to control feed rate, and tacrolimuss are carried out with micronizing, and is swashed using MALVERN2000 types
Light Particle Size Analyzer is measured to particle diameter distribution, controls particle diameter distribution D90For 8 μm, tacrolimuss micropowder is obtained, it is standby；
S2, by filler, disintegrating agent, the broken mesh sieve of mistake 100 of binding agent, it is standby；
S3, using efficient wet mixer-granulator by the tacrolimuss micropowder and the filler, disintegrating agent and bonding
Agent mixes, and is subsequently adding ethanol soft material, is pelletized using 30 mesh sieves, obtains wet granular；
S4, the wet granular is carried out into drying under reduced pressure at 45 DEG C, mistake is dried at 100 DEG C using fast tester for water content
Control, less than 1.5%, then with 30 mesh sieve granulate, to obtain dry particl again；
S5, by the dry particl and mix lubricant it is uniform after be filled in No. 4 gelatin softgel shells, obtain final product tacrolimuss rapid release
Preparation.
Embodiment 2
Formula：
| Raw material | Effect | Consumption |
| Tacrolimuss micropowder (D90=3 μm) | Main constituent | 1g |
| Polyethylene Glycol:Mannitol=0.5:1 (weight ratio) | Filler | 50g |
| Polydextrose:L- hydroxypropyl cellulose=1:0.25 (weight ratio) | Disintegrating agent | 8g |
| Hypromellose:Sodium carboxymethyl cellulose=0.2:1 (weight ratio) | Binding agent | 1g |
| Magnesium stearate | Lubricant | 1g |
Preparation method：
S1, control super micron mill admission pressure be 0.4Mpa, crushings pressure be 0.5Mpa, by tacrolimuss plus the excess of imports
In atomizer, it is 3g/ minutes to control feed rate, and tacrolimuss are carried out with micronizing, and using MALVERN2000 types
Laser particle size analyzer is measured to particle diameter distribution, controls particle diameter distribution D90For 5 μm, tacrolimuss micropowder is obtained, it is standby；
S2, by filler, disintegrating agent, the broken mesh sieve of mistake 100 of binding agent, it is standby；
S3, using efficient wet mixer-granulator by the tacrolimuss micropowder and the filler, disintegrating agent and bonding
Agent mixes, and is subsequently adding ethanol soft material, is pelletized using 24 mesh sieves, obtains wet granular；
S4, the wet granular is carried out into drying under reduced pressure at 40 DEG C, mistake is dried at 100 DEG C using fast tester for water content
Control, less than 1.5%, then with 24 mesh sieve granulate, to obtain dry particl again；
S5, by the dry particl and mix lubricant it is uniform after be filled in No. 4 gelatin softgel shells, obtain final product tacrolimuss rapid release
Preparation.
Embodiment 3
Formula：
| Raw material | Effect | Consumption |
| Tacrolimuss micropowder (D90=8 μm) | Main constituent | 1g |
| Polyethylene Glycol:Mannitol=1:1 (weight ratio) | Filler | 60g |
| Polydextrose:L- hydroxypropyl cellulose=1:0.45 (weight ratio) | Disintegrating agent | 6g |
| Hypromellose:Sodium carboxymethyl cellulose=0.6:1 (weight ratio) | Binding agent | 4g |
| Magnesium stearate | Lubricant | 2g |
Preparation method：
S1, control super micron mill admission pressure be 0.7Mpa, crushings pressure be 0.8Mpa, by tacrolimuss plus the excess of imports
In atomizer, it is 5g/ minutes to control feed rate, and tacrolimuss are carried out with micronizing, and is swashed using MALVERN2000 types
Light Particle Size Analyzer is measured to particle diameter distribution, controls particle diameter distribution D90For 10 μm, tacrolimuss micropowder is obtained, it is standby；
S2, by filler, disintegrating agent, the broken mesh sieve of mistake 100 of binding agent, it is standby；
S3, using efficient wet mixer-granulator by the tacrolimuss micropowder and the filler, disintegrating agent and bonding
Agent mixes, and is subsequently adding ethanol soft material, is pelletized using 30 mesh sieves, obtains wet granular；
S4, the wet granular is carried out into drying under reduced pressure at 50 DEG C, mistake is dried at 100 DEG C using fast tester for water content
Control, less than 1.5%, then with 30 mesh sieve granulate, to obtain dry particl again；
S5, by the dry particl and mix lubricant it is uniform after be filled in No. 4 gelatin softgel shells, obtain final product tacrolimuss rapid release
Preparation.
Embodiment 4
Formula：
| Raw material | Effect | Consumption |
| Tacrolimuss micropowder (D90=5 μm) | Main constituent | 1g |
| Polyethylene Glycol:Mannitol=0.5:1 (weight ratio) | Filler | 58g |
| Polydextrose:L- hydroxypropyl cellulose=1:0.35 (weight ratio) | Disintegrating agent | 6g |
| Hypromellose:Sodium carboxymethyl cellulose=0.4:1 (weight ratio) | Binding agent | 2g |
| Magnesium stearate | Lubricant | 1g |
Preparation method is with embodiment 1.
Comparative example 1
Formula：
| Raw material | Effect | Consumption |
| Tacrolimuss micropowder (D90=1 μm) | Main constituent | 1g |
| Polyethylene Glycol:Mannitol=0.8:1 (weight ratio) | Filler | 55g |
| Polydextrose:L- hydroxypropyl cellulose=1:0.35 (weight ratio) | Disintegrating agent | 6g |
| Hypromellose:Sodium carboxymethyl cellulose=0.4:1 (weight ratio) | Binding agent | 2g |
| Magnesium stearate | Lubricant | 1g |
Preparation method reference implementation example 1.
Comparative example 2
Formula：
| Raw material | Effect | Consumption |
| Tacrolimuss micropowder (D90=13 μm) | Main constituent | 1g |
| Polyethylene Glycol:Mannitol=0.8:1 (weight ratio) | Filler | 55g |
| Polydextrose:L- hydroxypropyl cellulose=1:0.35 (weight ratio) | Disintegrating agent | 6g |
| Hypromellose:Sodium carboxymethyl cellulose=0.4:1 (weight ratio) | Binding agent | 2g |
| Magnesium stearate | Lubricant | 1g |
Preparation method reference implementation example 1.
Comparative example 3
Formula：
| Raw material | Effect | Consumption |
| Tacrolimuss micropowder (D90=5 μm) | Main constituent | 1g |
| Polyethylene Glycol:Mannitol=0.8:1 (weight ratio) | Filler | 55g |
| Polydextrose | Disintegrating agent | 6g |
| Hypromellose:Sodium carboxymethyl cellulose=0.4:1 (weight ratio) | Binding agent | 2g |
| Magnesium stearate | Lubricant | 1g |
Preparation method reference implementation example 1.
Comparative example 4
Formula：
| Raw material | Effect | Consumption |
| Tacrolimuss micropowder (D90=5 μm) | Main constituent | 1g |
| Polyethylene Glycol:Mannitol=0.8:1 (weight ratio) | Filler | 55g |
| Polydextrose:L- hydroxypropyl cellulose=1:0.60 (weight ratio) | Disintegrating agent | 6g |
| Hypromellose:Sodium carboxymethyl cellulose=0.4:1 (weight ratio) | Binding agent | 2g |
| Magnesium stearate | Lubricant | 1g |
Preparation method reference implementation example 1.
Comparative example 5
Formula：
| Raw material | Effect | Consumption |
| Tacrolimuss micropowder (D90=5 μm) | Main constituent | 1g |
| Polyethylene Glycol:Mannitol=0.8:1 (weight ratio) | Filler | 55g |
| Polydextrose:L- hydroxypropyl cellulose=1:0.35 (weight ratio) | Disintegrating agent | 6g |
| Hypromellose | Binding agent | 2g |
| Magnesium stearate | Lubricant | 1g |
Preparation method reference implementation example 1.
Comparative example 6
Formula：
| Raw material | Effect | Consumption |
| Tacrolimuss micropowder (D90=5 μm) | Main constituent | 1g |
| Polyethylene Glycol:Mannitol=0.8:1 (weight ratio) | Filler | 55g |
| Polydextrose:L- hydroxypropyl cellulose=1:0.35 (weight ratio) | Disintegrating agent | 6g |
| Hypromellose:Sodium carboxymethyl cellulose=1:1 (weight ratio) | Binding agent | 2g |
| Magnesium stearate | Lubricant | 1g |
Preparation method reference implementation example 1.
Comparative example 7
Formula：
| Raw material | Effect | Consumption |
| Tacrolimuss micropowder (D90=5 μm) | Main constituent | 1g |
| Mannitol | Filler | 55g |
| Crospovidone | Disintegrating agent | 6g |
| Hypromellose | Binding agent | 2g |
| Magnesium stearate | Lubricant | 1g |
Preparation method reference implementation example 1.
Test example one
Sample (specification is 1mg) prepared by embodiment 1～3 grinds commercially available product (Astellas Pharma Inc, business with original
The name of an article：Prograf, specification 1mg, lot number：Quality versus' research 1D5812A) is carried out, is as a result prepared according to embodiment 1～3
Sample indices grind that commercially available product is basically identical with original, and concrete outcome is shown in Table 1.
The embodiment 1～3 of table 1 grinds commercially available product quality versus' result with original
Test example two
Sample (specification 1mg) prepared by embodiment 1～4, comparative example 1～7 is ground into commercially available product with original, and (Astellas pharmacy has
Limit company, trade name：Prograf, specification 1mg, lot number：1D5812A), carry out according to Chinese Pharmacopoeia two annex of version in 2010
In-vitro release curves compare, and concrete outcome is shown in Table 2～4.
The release in vitro result of sample prepared by 2 embodiment of table 1～3
The release in vitro result of sample prepared by 3 comparative example of table 1～4
Sample and original prepared by 4 comparative example of table 5～7 grinds commercially available product release in vitro result
From upper table 2～4, the crude drug of different-grain diameter and different prescription components, its release profiles differs greatly, when
Micronizing (controlling particle diameter distribution D90 for 3～8 μm) is adopted, while adopting the special prescription component of the present invention (with certain proportion
Polyethylene Glycol and Mannitol compositionss as filler, with a certain proportion of polydextrose and the group of L- hydroxypropyl celluloses
Compound as disintegrating agent, using the compositionss of a certain proportion of hypromellose and sodium carboxymethyl cellulose as binding agent, with
Magnesium stearate is used as lubricant) obtained in tacrolimuss quick releasing formulation sample (such as embodiment 1～4), its sample grinds commercially available with original
Product In-vitro release curves concordance preferably (similar factors f2 are more than 70), and homogeneity good (with RSD judgements) is discharged, with commercially available product
Similar even better than commercially available product.In embodiment 1～4, the result of extraction of embodiment 1 is preferable and dissolution homogeneity is optimal, and dissolution
Behavior is closest to commercially available product, therefore embodiment 1 is highly preferred embodiment of the present invention.
When crude drug particle diameter distribution is controlled in D90More than 10 μm (comparative examples 2) or D90During less than 3 μm (comparative example 1), its
The In-vitro release curves inconsistent (similar factors f2 are less than 50) that sample grinds commercially available product with original, analysis reason is that tacrolimuss are difficult
Soluble drug, when particle diameter increases, causes rate of dissolution to reduce, so as to vitro release slows down.When tacrolimuss raw material particle size
When distribution is excessively tiny (D90 be less than 3 μm), in theory particle diameter reduces its dissolubility and can increase, but because raw material particle size it is too small, its medicine
The quality of thing microgranule mitigates, and rapid flotation, in release medium surface, adds him after disintegrate dispersion from preparation to cause drug microparticles
Ke Mosi raw material hydrophobicitys are strong so as to drug microparticles cannot moistening cause its release low.
When crude drug Particle Distribution is in D90At 3～8 μm, sample (comparative example 7), its sample are prepared using customary adjuvant component
The In-vitro release curves difference that product grind commercially available product with original is also larger, if while to currently preferred formulation components (with a definite proportion
The Polyethylene Glycol of example and the compositionss of Mannitol as filler, with a certain proportion of polydextrose and L- hydroxypropyl celluloses
Compositionss as disintegrating agent, the compositionss using a certain proportion of hypromellose and sodium carboxymethyl cellulose as binding agent,
Using magnesium stearate as lubricant) it is replaced or reduces some components or changes component ratio (comparative example 3～6), its
Sample with original grind commercially available product In-vitro release curves difference it is also larger, illustrate employing present invention determine that crude drug particle diameter distribution control
System is in D90At 3～8 μm, and while using the present invention formulation components prepare sample, just can guarantee that its In-vitro release curves with
It is consistent that original grinds commercially available product.
Test example three
Sample (specification is 1mg) prepared by embodiment 1～3, comparative example 3～7 is ground into commercially available product (Astellas pharmacy with original
Company limited, trade name：Prograf, specification 1mg, lot number：1D5812A) carry out stability (30 DEG C ± 2 DEG C, relative humidity
65% ± 5%) comparative study, mainly investigates to the Key Quality attribute (impurity and dissolution) of product, as a result according to this
Sample prepared by inventive embodiments 1～3 grinds commercially available product and places 12 under the conditions of 30 DEG C ± 2 DEG C, relative humidity 65% ± 5% with original
Individual month, impurity and dissolution did not changed substantially, illustrated that the sample prepared according to the embodiment of the present invention 1～3, original grind commercially available product
Quality is more stable.But the sample of the preparation of documents 3～7, after 12 months, its impurity content increases, molten
Out-degree also there occurs significantly change, and illustrating the basic components of the preparation of comparative example 3～7 can not only affect the tacrolimuss micro-
The dissolved corrosion of powder, can also affect the stability of its system.Concrete outcome is shown in Table 5 and table 6.
The embodiment 1～3 of table 5 and original grind commercially available product stability comparing result (30 DEG C ± 2 DEG C, relative humidity 65% ± 5%)
The stability result of 6 comparative example of table 3～7 (30 DEG C ± 2 DEG C, relative humidity 65% ± 5%)
Above-described embodiment is the present invention preferably embodiment, but embodiments of the present invention not by above-described embodiment
Limit, other any spirit without departing from the present invention and the change, modification, replacement made under principle, combine, simplification,
Equivalent substitute mode is should be, is included within protection scope of the present invention.
Claims (3)
1. a kind of tacrolimuss quick releasing formulation, it is characterised in that including the raw material of following weight portion meter：Tacrolimuss micropowder 0.5
0.5～2 part of～1.5 parts, 50～60 parts of filler, 4～8 parts of binding agent, 1～4 part of disintegrating agent and lubricant；
Particle diameter distribution D of the tacrolimuss micropowder90For 3～8 μm；
The filler be the compositionss of Polyethylene Glycol and Mannitol, the Polyethylene Glycol and Mannitol weight ratio for (0.5～
1.0):1；
The disintegrating agent is the compositionss of polydextrose and L- hydroxypropyl celluloses, the polydextrose and L- hydroxypropyl celluloses
Weight ratio be 1:(0.25～0.45)；
Described adhesive is the compositionss of hypromellose and sodium carboxymethyl cellulose, the hypromellose and carboxymethyl
The weight ratio of sodium cellulosate is (0.2～0.6):1；
The lubricant is magnesium stearate.
2. tacrolimuss quick releasing formulation according to claim 1, it is characterised in that including the raw material of following weight portion meter：
1 part of 1 part of tacrolimuss micropowder, 55 parts of filler, 6 parts of binding agent, 2 parts of disintegrating agent and lubricant.
3. a kind of method for preparing tacrolimuss quick releasing formulation as claimed in claim 1 or 2, it is characterised in that including following
Step：
S1, control super micron mill admission pressure be 0.4～0.7Mpa, crushings pressure be 0.5～0.8Mpa, by tacrolimuss
In adding super micron mill, it is 3g～5g/ minutes to control feed rate, and tacrolimuss are carried out with micronizing, control particle diameter point
Cloth D90For 3～8 μm, tacrolimuss micropowder is obtained, it is standby；
S2, by filler, disintegrating agent, the broken mesh sieve of mistake 100 of binding agent, it is standby；
S3, the tacrolimuss micropowder and the filler, disintegrating agent and binding agent are mixed using efficient wet mixer-granulator
Close, be subsequently adding ethanol soft material, pelletized using 24～30 mesh sieves, obtain wet granular；
S4, the wet granular is carried out into drying under reduced pressure at 40 DEG C～50 DEG C, using drying of the fast tester for water content at 100 DEG C
Weightlessness control, then with 24～30 mesh sieve granulate, obtains dry particl less than 1.5%；
S5, by the dry particl and mix lubricant it is uniform after be filled in capsule shells, obtain final product tacrolimuss quick releasing formulation.
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| CN111991369B (en) * | 2020-09-11 | 2022-03-25 | 南京瑞捷医药科技有限公司 | Tacrolimus sustained-release pellet and preparation method and application thereof |
| CN115804760A (en) * | 2022-11-23 | 2023-03-17 | 无锡福祈制药有限公司 | Tacrolimus nanocrystal capsule and preparation method thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1820759A (en) * | 2006-03-20 | 2006-08-23 | 复旦大学 | Tacrolimus solid dispersion and its preparing method |
| CN104771380A (en) * | 2015-04-20 | 2015-07-15 | 山东新时代药业有限公司 | Tacrolimus capsule capable of being rapidly dissolved out |
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2015
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1820759A (en) * | 2006-03-20 | 2006-08-23 | 复旦大学 | Tacrolimus solid dispersion and its preparing method |
| CN104771380A (en) * | 2015-04-20 | 2015-07-15 | 山东新时代药业有限公司 | Tacrolimus capsule capable of being rapidly dissolved out |
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