CN107913411B - Ai Qubo Pa inclusion compound, its preparation and preparation method - Google Patents
Ai Qubo Pa inclusion compound, its preparation and preparation method Download PDFInfo
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- CN107913411B CN107913411B CN201710912770.7A CN201710912770A CN107913411B CN 107913411 B CN107913411 B CN 107913411B CN 201710912770 A CN201710912770 A CN 201710912770A CN 107913411 B CN107913411 B CN 107913411B
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/415—1,2-Diazoles
- A61K31/4152—1,2-Diazoles having oxo groups directly attached to the heterocyclic ring, e.g. antipyrine, phenylbutazone, sulfinpyrazone
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Abstract
The invention provides a Ai Qubo Pa inclusion compound, a preparation and a preparation method thereof, wherein the Ai Qubo Pa inclusion compound comprises the following components: ai Qubo Pa or pharmaceutically acceptable salt thereof, and inclusion material, wherein the inclusion material is cyclodextrin or derivatives thereof. The inclusion compound provided by the invention can reduce the contact between multivalent metal ions and Ai Qubo Pa, thereby reducing the formation of chelate; and improves the solubility of the medicine. The preparation prepared from the inclusion compound and other pharmaceutically acceptable auxiliary materials can improve the dissolution rate of the medicine, is beneficial to the absorption of Ai Qubo Pa medicine, increases the flexibility and the compliance of the patient in taking medicine, and can avoid the reduction or even ineffectiveness of the curative effect caused by improper medicine taking, thereby ensuring the normal play of the medicine effect. In addition, the preparation method of the Ai Qubo Pa inclusion compound provided by the invention has the advantages of high inclusion rate, low production cost and simple process, and is suitable for industrial production.
Description
Technical Field
The invention relates to the field of pharmaceutical preparations, in particular to an eriopap inclusion compound, a preparation and a preparation method thereof.
Background
Ai Qubo Pa is used for treating thrombocytopenia of chronic Idiopathic Thrombocytopenic Purpura (ITP) patients after glucocorticoid medicine, immunoglobulin treatment inefficiency or splenectomy, thrombocytopenia of chronic hepatitis C patients, severe aplastic anemia due to insufficient response to immunosuppressive treatment, etc.
Ai Qubo Pa is administered 1 day and 1 time, and should be orally administered orally on an empty stomach, i.e. 1 hr before or 2 hr after meals, and no medicine or substance containing polyvalent metal ion (such as iron ion, calcium ion, zinc ion, magnesium ion) such as antacid, calcium ion-enriched product, mineral supplement, etc. can be administered before and after 4 hr. Thus, research on Ai Qubo Pa medicine is still in progress.
Disclosure of Invention
The present invention aims to solve at least one of the technical problems in the related art to some extent.
The present invention has been completed based on the following findings by the inventors:
the present inventors have found during the course of the study that the effect of Ai Qubo Pa is greatly affected by the polyvalent metal ion contained in the food. Clinical data in Ai Qubo pa FDA review file show: when taken together with food, the AUC (0- ≡) of Ai Qubo Pa medicine is reduced by 59%, and Cmax is reduced by 65%; while Ai Qubo Pa reduced AUC (0- ≡) and Cmax by about 70% when taken with antacid; these are all because multivalent metal ions contained in foods or antacids can undergo chelation reaction with Ai Qubo Pa, thereby severely reducing drug absorption. In addition, the inventors have unexpectedly found that the in vitro dissolution data of Ai Qubo Pa shows that the dissolution rate of tablets containing multivalent metal ions is significantly slower than tablets without metal ions. In conclusion, ai Qubo Pa is a drug which is difficult to dissolve and is slow to dissolve; when the multivalent metal ions are encountered, the chelation effect further occurs, and the dissolution speed of the medicine is further reduced, so that the absorption of the medicine is reduced, and the medicine effect of Ai Qubo Pa is not exerted.
The inventor of the invention has intensively studied to find that, on one hand, the inclusion of Ai Qubo Pa in the cavity of the inclusion material by the inclusion technique can reduce the contact between multivalent metal ions and Ai Qubo Pa and reduce the formation of chelate; in addition, ai Qubo Pa is a poorly water-soluble drug, and can increase the solubility of Ai Qubo Pa after inclusion.
On the other hand, the Ai Qubo Pa inclusion compound can prevent the medicine from being influenced by metal ions even if taken together with food, and achieve the effect similar to that of taking on an empty stomach, thereby reducing excessive medicine taking limit, increasing the flexibility and the compliance of taking medicine for patients, avoiding the decrease and even ineffectiveness of the curative effect caused by improper medicine taking and ensuring the normal play of the medicine effect.
Accordingly, the present invention has been made in view of the above problems, and an object of the present invention is to provide an eriopapain clathrate and a pharmaceutical preparation having high drug administration flexibility, good drug dissolution rate, or normal drug efficacy by being taken together with food or the like.
In a first aspect of the invention, the invention proposes an etrpopal clathrate according to an embodiment of the invention, comprising: ai Qubo Pa or pharmaceutically acceptable salts and inclusion materials thereof; the inclusion material is cyclodextrin or its derivative.
The inventors have unexpectedly found that, by adopting the Ai Qubo Pa inclusion compound of the embodiment of the invention to include Ai Qubo Pa in a cavity of cyclodextrin or a derivative thereof by an inclusion technology, not only the contact between polyvalent metal ions and Ai Qubo Pa can be reduced, the formation of chelate can be effectively reduced, but also the solubility of Ai Qubo Pa after inclusion can be increased, the dissolution end point of Ai Qubo Pa can be improved, the bioavailability of the drug can be further improved, and the purpose of promoting the normal exertion of the drug effect of Ai Qubo Pa can be achieved.
Those skilled in the art will appreciate that Ai Qubo Pa or a pharmaceutically acceptable salt thereof refers to 3' - [ (2Z) - [1- (3, 4-dimethylphenyl) -1, 5-dihydro-3-methyl-5-oxo-4H-pyrazol-4-ylidene]Hydrazino radicals]-2-hydroxy- [1,1' -biphenyl]-3-carboxylic acid or a salt thereof with an additively acid or base. While Ai Qubo Pa is a chelating agent of hydroxyaminocarboxylic acids, whose chemical structure is capable of binding amino, hydroxy and carboxyl groups to polyvalent metal ions (e.g. Fe 3+ 、Ca 2+ 、Zn 2+ And Mg (magnesium) 2+ Etc.) to form a poorly soluble chelate compound. Thus, ai Qubo Pa has chelating effect with multivalent metal ions in food or antacid, and the chelate is more than normalThe substance is more stable, thereby affecting the dissolution rate and absorption effect of Ai Qubo Pa.
The cyclodextrin or its derivative according to the present invention includes, but is not limited to, α -cyclodextrin, β -cyclodextrin, γ -cyclodextrin, hydroxyethyl- β -cyclodextrin, hydroxypropyl- β -cyclodextrin, dihydroxy- β -cyclodextrin, methyl- β -cyclodextrin, dimethyl- β -cyclodextrin, sulfobutyl-yl cyclodextrin, glucose cyclodextrin, maltose cyclodextrin, carboxymethyl cyclodextrin and sulfoalkyl cyclodextrin.
The inventors have unexpectedly found that the Ai Qubo Pa inclusion compound of the present invention is mainly prepared by inclusion of drug molecules in the cavity structure of the inclusion material to form a specific complex, thereby blocking chelation between Ai Qubo Pa and polyvalent metal ions. In addition, the medicine loses the original crystallinity in the inclusion compound, so that the medicine enters into the gaps of the inclusion compound in a molecular state, the medicine has high dispersity, and the inclusion material usually contains a plurality of hydrophilic alcoholic hydroxyl groups, so that the inclusion compound has good wettability, and the solubilization effect on the medicine can be achieved; and the molecular medicine is easy to penetrate the biological film, so that the bioavailability of the medicine can be improved.
In addition, the Ai Qubo Pa inclusion compound according to the embodiment of the invention can also have the following additional technical characteristics:
according to an embodiment of the invention, the inclusion material comprises at least one selected from the group consisting of α, β, γ -cyclodextrin and derivatives thereof. Therefore, the cyclodextrin or the derivative of the embodiment of the invention is used as an inclusion material, so that the chelating effect can be effectively reduced, the water solubility of the medicine is improved, the bioavailability of the medicine is improved, and the effect of the medicine is normally exerted without being influenced by food.
According to the embodiment of the invention, the weight ratio of Ai Qubo Pa to the inclusion material is as follows: 1:1-1:51. Therefore, the inclusion material with the specific content can effectively reduce the chelating effect, improve the water solubility of the medicine, improve the bioavailability of the medicine, and can normally exert the curative effect without being influenced by food.
In a second aspect of the invention, the invention provides a pharmaceutical formulation prepared from the Ai Qubo Pa inclusion compound.
According to an embodiment of the invention, the pharmaceutical formulation is an oral formulation.
The inventors have unexpectedly found that with the oral preparation of the embodiment of the present invention, even if the oral preparation is taken together with a substance or a drug containing a polyvalent metal ion such as food, antacid, etc., the effect of taking Ai Qubo Pa for a long period of time can be ensured. Those skilled in the art will appreciate that the features and advantages described above for the Ai Qubo pa clathrate are still applicable to the oral formulation and will not be described in detail herein.
In addition, the oral preparation according to the above embodiment of the present invention may further have the following additional technical features:
according to an embodiment of the present invention, the oral preparation further contains pharmaceutically acceptable excipients. The oral preparation further comprises pharmaceutically acceptable auxiliary materials selected from at least one of a filler, a disintegrating agent and a lubricant.
According to an embodiment of the present invention, the filler comprises at least one selected from the group consisting of microcrystalline cellulose, powdered cellulose, lactose, pregelatinized starch, lactitol, mannitol, sorbitol, maltodextrin, magnesium aluminum silicate, anhydrous dibasic calcium phosphate, and calcium carbonate; the disintegrating agent comprises at least one selected from corn starch, pregelatinized starch, modified corn starch, croscarmellose sodium, crospovidone, sodium carboxymethyl starch, methylcellulose, microcrystalline cellulose, modified cellulose gum, agar, guar gum, and hydroxymethyl cellulose and salts thereof; the lubricant comprises at least one selected from the group consisting of talc, magnesium stearate, stearic acid, colloidal silicon dioxide, mineral oil, wax, sodium stearyl fumarate, glyceryl behenate, polyethylene glycol, and hydrogenated vegetable oil. The inventor surprisingly discovers that the adoption of various medicinal auxiliary materials in the embodiment of the invention can promote the normal exertion of the medicinal effect of the active ingredient Ai Qubo Pa in the medicinal composition, and is convenient for the production, transportation, storage and administration of medicaments. For example, the added filler can promote easier molding of the medicine and is convenient for patients to take; the disintegrating agent has strong affinity with water, and can be rapidly split after the medicine enters the digestive tract, thereby promoting the rapid release of active substances; the adhesive can firmly pack the medicinal components together, so that the mechanical property of the medicament is improved and the medicament is convenient to transport; the lubricant can reduce the surface tackiness of the drug during the production process and is not easy to stick together. According to embodiments of the present invention, the oral formulations include tablets, pills, capsules, granules and dry suspensions.
According to an embodiment of the invention, the tablet is a gastric or enteric coated tablet.
According to an embodiment of the invention, the tablet is a gastric or enteric coated tablet.
According to an embodiment of the invention, the pill is a gastric or enteric pill.
According to an embodiment of the invention, the capsule is a gastric capsule or an enteric capsule.
According to an embodiment of the present invention, the granule is a gastric-soluble granule or an enteric granule.
According to the embodiment of the invention, the dry suspension is a gastric dry suspension or an enteric dry suspension.
Thus, with the various types of oral preparations according to the embodiments of the present invention, even if the oral preparation is taken together with a substance or a drug containing a polyvalent metal ion such as food, antacid, etc., the effect of taking Ai Qubo Pa over a long period of time can be sufficiently ensured.
According to an embodiment of the invention, the Ai Qubo Pa content is 2-40 wt%, based on the total weight of the pharmaceutical formulation; the inclusion material content is 2-90 wt%; the content of the filler is 10-90 wt%; the content of the disintegrant is not more than 20% by weight; the lubricant is present in an amount of no more than 2% by weight. Therefore, by adopting various pharmaceutical excipients with a certain proportion, the invention can further promote the normal play of the efficacy of the active ingredient Ai Qubo Pa in the pharmaceutical composition, and is more beneficial to the production, transportation and administration of the medicine.
According to an embodiment of the present invention, ai Qubo Pa is present in an amount of 12.76 wt%, the inclusion material is present in an amount of 47.74 wt%, the filler is present in an amount of 30.50 wt%, the disintegrant is present in an amount of 8.00 wt%, and the lubricant is present in an amount of 1.00 wt%, based on the total weight of the pharmaceutical preparation. Therefore, by adopting various medicinal auxiliary materials with a certain proportion, the invention can further promote the normal play of the medicinal effect of the active ingredient Ai Qubo Pa in the medicinal composition, and is more beneficial to the production, storage, transportation and administration of the medicament.
In a third aspect of the present invention, the present invention provides a method for preparing the inclusion compound. The method is at least one of saturated water solution method, grinding method, ultrasonic method, freeze drying method, spray drying method and reduced pressure drying method. Therefore, the inclusion compound prepared by the preparation method provided by the embodiment of the invention has the advantages of high inclusion rate, low production cost and simple process, and is suitable for industrial production.
According to an embodiment of the invention, the method is a freeze-drying method: weighing the components respectively, completely dissolving the inclusion material in water, adding the medicine, stirring, centrifuging, collecting supernatant, and freeze-drying the supernatant to obtain the inclusion compound. Therefore, the inclusion compound prepared by the preparation method provided by the embodiment of the invention has the advantages of high inclusion rate, low production cost and simple process, and is suitable for industrial production.
Additional aspects and advantages of the invention will be set forth in part in the description which follows, and in part will be obvious from the description, or may be learned by practice of the invention.
Definition of terms
"SDS" in the present invention means sodium dodecyl sulfate unless otherwise specified;
in the present invention, "room temperature" means a temperature range of 10℃to 30 ℃.
The term "C" as used herein max "means the highest plasma concentration measured during the sampling interval.
The term "T" as used herein max "is measured after administration to C max Is a time of (a) to be used.
The term "AUC" as used herein refers to the average area under the plasma drug concentration versus time curve.
Detailed Description
The following examples are set forth in detail, and it will be understood by those skilled in the art that the following examples are intended to illustrate the invention and should not be construed as limiting the invention. Unless specifically stated otherwise, specific techniques or conditions are not explicitly described in the following examples, and may be performed according to techniques or conditions commonly used in the art or according to product specifications by those skilled in the art. The medicines, reagents or instruments used are common products which are commercially available without identifying manufacturers.
Unless explicitly stated, the following detection methods and preparation processes were employed in the following examples:
in-vitro dissolution detection instrument and detection method
HPLC instrument model: agilent 1260;
chromatographic conditions: the detection wavelength is UV228nm, the chromatographic column adopts Thermo BDS HYPERSIL C184.6mm×50mm,2.4 micrometers, the flow rate is 1.0mL/min, the sample injection amount is 10 microliters, and the running time is 5.2min.
In-vivo data detection instrument and detection method
LC-MS/MS instrument model: AB Sciex API4000
Chromatographic conditions: the chromatographic column adopts ase:Sub>A waters xbridge C18EB-A-1011,2.5 micrometers, the flow rate is 0.4mL/min, the sample injection amount is 20 microliters, the running time is 4min, and the ionization model is as follows: -ESI.
Preparation of inclusion compound: including but not limited to freeze drying: weighing the components respectively, completely dissolving the inclusion material in water, adding the medicine, stirring, centrifuging, collecting supernatant, and freeze-drying the supernatant to obtain the inclusion compound.
Preparation of the capsules: including but not limited to powder methods: specifically, each composition is weighed, ai Qubo Pa is prepared into an inclusion compound according to the inclusion compound preparation method, the inclusion compound is sieved, a disintegrating agent and a part of filler are added, the mixture is mixed, the rest of filler is added, the mixture is mixed, finally a lubricant is added, and the mixture is uniformly mixed and then filled into a capsule (an enteric capsule or a gastric sol capsule), so that the capsule for an in-vitro dissolution test is obtained.
Preparation of tablets: including but not limited to powder direct compression methods: specifically, each composition is weighed, ai Qubo Pa is prepared into an inclusion compound according to the inclusion compound preparation method, after the inclusion compound is screened, a disintegrating agent and a part of filler are added, the mixture is mixed, the rest of filler is added, the mixture is mixed, finally a lubricant is added, and after uniform mixing, the tablet for an in vitro dissolution test is obtained by tabletting.
In the embodiment of the invention, the medicine is in the form of a tablet or a capsule, and has little influence on the dissolution rate of Ai Qubo Pa, and can be ignored. It should be noted that the medicines in the embodiment of the invention are all plain tablets, and the actual pharmaceutical process can also adopt the step of coating.
Comparative example 1
In the comparative example, ai Qubo Pa tablets are prepared according to a powder direct tabletting method and the following table, the components are weighed respectively, ai Qubo Pa and microcrystalline cellulose are mixed for 5min, mannitol is added for 5min, croscarmellose sodium is added for 5min, magnesium stearate is added for 5min, and tabletting is carried out, thus obtaining Ai Qubo Pa tablets which are not treated by the containing technology.
| Prescription composition | Prescription proportion (wt.%) |
| Ai Qubo Pa ethanolamine | 12.76 |
| Mannitol (mannitol) | 65.24 |
| Microcrystalline cellulose | 13.00 |
| Croscarmellose sodium | 8.00 |
| Magnesium stearate | 1.00 |
| Totals to | 100.00 |
Then, ai Qubo Pa tablets were respectively put into a pH6.8 phosphate buffer solution (not containing a calcium medium) containing 0.5% by weight of SDS, a pH6.8 phosphate buffer solution (containing a calcium medium) containing 2.78mmol/L of calcium chloride and containing 0.5% by weight of SDS, and then subjected to elution test using a elution machine at 75rpm using USP II (i.e., paddle method described in United states pharmacopoeia). Finally, taking a dissolution end point solution, filtering the solution by using a 0.45-micrometer microporous filter membrane, taking subsequent filtrate, and respectively carrying out HPLC test on the two filtrate.
The elution results of this comparative example are shown in Table 1. As can be seen from Table 1, the tablets without treatment containing Ai Qubo Pa had a dissolution end point of 98% in a phosphate buffer solution of pH6.8 (without calcium-containing medium) containing 0.5% by weight of SDS, whereas the dissolution end point in a phosphate buffer solution of pH6.8 (with calcium-containing medium) containing 2.78mmol/L of calcium chloride and 0.5% by weight of SDS was only 64%; the dissolution effect of calcium ions on the comparative example 1 is obvious, the dissolution rate is slow, the cumulative dissolution percentage of 15min is only 50%, and the dissolution effect of the calcium ions on Ai Qubo Pa is fully demonstrated to be obvious.
Example 1
In this example, according to the preparation process and test conditions described above, a solution of Ai Qubo Pa inclusion compound in a pH6.8 phosphate buffer solution containing 0.5 wt% SDS, a solution of 2.78mmol/L calcium chloride and a pH6.8 phosphate buffer solution medium containing 0.5 wt% SDS was subjected to filtration, and then HPLC test was performed on each of the two filtrates. Wherein, the specific composition of the inclusion compound is as follows:
| prescription composition | Prescription proportion (wt.%) |
| Ai Qubo Pa ethanolamine | 1.43 |
| Alpha-cyclodextrin | 8.96 |
| Purified water | 89.61 |
| Totals to | 100.00 |
In the embodiment, preparing an inclusion compound by adopting a freeze drying method, respectively weighing, wherein the weight ratio of Ai Qubo Pa to alpha-cyclodextrin is 1:6.3, dissolving the alpha-cyclodextrin in purified water, dissolving Ai Qubo Pa in alpha-cyclodextrin water solution after the solution is clarified, stirring for 3 hours at room temperature, centrifuging at 8000rpm for 5min by using a centrifugal machine, taking supernatant, freeze-drying the supernatant to obtain the inclusion compound, and determining the inclusion compound according to an inclusion rate calculation formula: inclusion rate (%) = measured content/theoretical content x 100%, the inclusion rate of the obtained eriobopa inclusion compound was 97.3%.
The elution results of this example are shown in Table 1. As can be seen from Table 1, the Ai Qubo Pa inclusion compound included by α -cyclodextrin had a dissolution end point of 102% in a phosphate buffer solution (not containing calcium medium) of pH6.8 containing 0.5% by weight of SDS, and a dissolution end point of 95% in a phosphate buffer solution (containing calcium medium) of pH6.8 containing 2.78mmol/L of calcium chloride and 0.5% by weight of SDS. The Ai Qubo Pa after inclusion treatment is described, so that the contact of polyvalent metal ions and Ai Qubo Pa can be reduced, the formation of chelate can be effectively reduced, the solubility of Ai Qubo Pa after inclusion can be increased, the dissolution end point of Ai Qubo Pa can be improved, the bioavailability of the medicine can be further improved, and the purpose of promoting the normal exertion of the drug effect of Ai Qubo Pa can be achieved.
Example 2
In this example, according to substantially the same production process and test conditions as in example 1, after a solution of Ai Qubo Pa inclusion compound dissolved in a pH6.8 phosphate buffer solution containing 0.5% by weight of SDS and a pH6.8 phosphate buffer solution medium containing 0.5% by weight of SDS and containing 2.78mmol/L of calcium chloride was subjected to filtration, HPLC test was performed on each of the two filtrates. The difference is that in this example, the specific composition of the Ai Qubo Pa inclusion compound is as follows:
| prescription composition | Prescription proportion (wt.%) |
| Ai Qubo Pa ethanolamine | 1.48 |
| Beta-cyclodextrin | 16.42 |
| Purified water | 82.10 |
| Totals to | 100.00 |
And Ai Qubo Pa and beta-cyclodextrin are 1:11.1 by weight, ai Qubo Pa are dissolved in beta-cyclodextrin water solution, and then stirred in water bath at 70 ℃. The inclusion rate of the Ai Qubo Pa inclusion compound is 77.7 percent.
The elution results of this example are shown in Table 1. As can be seen from Table 1, ai Qubo Pa inclusion compound included by beta-cyclodextrin,
the dissolution end point in the phosphate buffer solution (without calcium-containing medium) at pH6.8 containing 0.5 wt% SDS was substantially identical to the dissolution end point in the phosphate buffer solution (with calcium-containing medium) at pH6.8 containing 2.78mmol/L calcium chloride and 0.5 wt% SDS. The Ai Qubo Pa which is subjected to beta-cyclodextrin inclusion treatment is described, so that the contact of polyvalent metal ions and Ai Qubo Pa can be reduced, the formation of chelate can be effectively reduced, the solubility of Ai Qubo Pa after inclusion can be increased, and the dissolution end point of Ai Qubo Pa can be improved, so that the bioavailability of the medicine can be improved, and the purpose of promoting the normal exertion of the drug effect of Ai Qubo Pa can be achieved.
Example 3
In this example, according to substantially the same production process and test conditions as in example 1, after a solution of Ai Qubo Pa inclusion compound dissolved in a pH6.8 phosphate buffer solution containing 0.5% by weight of SDS and a pH6.8 phosphate buffer solution medium containing 0.5% by weight of SDS and containing 2.78mmol/L of calcium chloride was subjected to filtration, HPLC test was performed on each of the two filtrates. The difference is that in this example, the specific composition of the Ai Qubo Pa inclusion compound is as follows:
| prescription composition | Prescription proportion (wt.%) |
| Ai Qubo Pa ethanolamine | 4.00 |
| Gamma-cyclodextrin | 16.00 |
| Purified water | 80.00 |
| Totals to | 100.00 |
And Ai Qubo Pa and gamma-cyclodextrin are mixed in a weight ratio of 1:4, ai Qubo Pa is dissolved in gamma-cyclodextrin water solution, and then the mixture is stirred in a water bath at 70 ℃. The inclusion rate of the Ai Qubo Pa inclusion compound is 100%.
The elution results of this example are shown in Table 1. As can be seen from Table 1, ai Qubo Pa inclusion compound included by gamma-cyclodextrin,
the dissolution end point in the phosphate buffer solution (without calcium-containing medium) at pH6.8 containing 0.5 wt% SDS was substantially identical to the dissolution end point in the phosphate buffer solution (with calcium-containing medium) at pH6.8 containing 2.78mmol/L calcium chloride and 0.5 wt% SDS. The Ai Qubo Pa after inclusion treatment is illustrated, so that the contact of polyvalent metal ions and Ai Qubo Pa can be reduced, the formation of chelate can be effectively reduced, the solubility of Ai Qubo Pa after inclusion can be increased, and the dissolution end point of Ai Qubo Pa can be improved, so that the bioavailability of the medicine can be improved, and the purpose of promoting the normal exertion of the drug effect of Ai Qubo Pa can be achieved.
Example 4
In this example, according to substantially the same production process and test conditions as in example 1, after a solution of Ai Qubo Pa inclusion compound dissolved in a pH6.8 phosphate buffer solution containing 0.5 wt% SDS and a pH6.8 phosphate buffer solution medium containing 0.5 wt% SDS containing 2.78mmol/L calcium chloride was filtered, HPLC test was performed on each of the two filtrates. The difference is that in this example, the specific composition of the Ai Qubo Pa inclusion compound is as follows:
| prescription composition | Prescription proportion (wt.%) |
| Ai Qubo Pa ethanolamine | 0.50 |
| Beta-cyclodextrin | 24.88 |
| Purified water | 74.62 |
| Totals to | 100.00 |
And the weight ratio of Ai Qubo Pa to beta-cyclodextrin is 1:50. The inclusion rate of the Ai Qubo Pa inclusion compound is 100%.
The elution results of this example are shown in Table 1. As can be seen from Table 1, the Ai Qubo Pa inclusion compound included by the beta-cyclodextrin had a dissolution end point at pH6.8 phosphate buffer solution (without calcium-containing medium) containing 0.5 wt% SDS, which was substantially identical to a dissolution end point at pH6.8 phosphate buffer solution (with calcium-containing medium) containing 2.78mmol/L calcium chloride and 0.5 wt% SDS. The Ai Qubo Pa after inclusion treatment is illustrated, so that the contact of polyvalent metal ions and Ai Qubo Pa can be reduced, the formation of chelate can be effectively reduced, the solubility of Ai Qubo Pa after inclusion can be increased, and the dissolution end point of Ai Qubo Pa can be improved, so that the bioavailability of the medicine can be improved, and the purpose of promoting the normal exertion of the drug effect of Ai Qubo Pa can be achieved.
Example 5
In this example, ai Qubo Pa inclusion compound was prepared by the same preparation method as in example 3, and then capsules were prepared and the same test conditions were carried out, and after dissolving Ai Qubo Pa inclusion compound capsules in a solution of 0.5 wt% SDS in pH6.8 phosphate buffer solution and 2.78mmol/L calcium chloride in a pH6.8 phosphate buffer solution medium containing 0.5 wt% SDS, HPLC test was carried out on each of the two filtrates. The difference is that in this example, the specific composition of the Ai Qubo Pa inclusion capsule is as follows:
| prescription composition | Prescription proportion (wt.%) |
| Ai Qubo Pa ethanolamine | 12.76 |
| Gamma-cyclodextrin | 47.74 |
| Mannitol (mannitol) | 17.50 |
| Microcrystalline cellulose | 13.00 |
| Croscarmellose sodium | 8.00 |
| Magnesium stearate | 1.00 |
| Totals to | 100.00 |
The Ai Qubo Pa inclusion compound capsule is prepared by a powder method, wherein Ai Qubo Pa inclusion compound is firstly sieved by a 40-mesh sieve, then crosslinked sodium carboxymethyl cellulose and microcrystalline cellulose are added to be mixed for 10min, mannitol is added to be mixed for 10min, finally magnesium stearate is added to be mixed for 5min, the mixture is uniformly mixed, and the mixture is filled into capsules to obtain Ai Qubo Pa capsules.
The elution results of this example are shown in Table 1. As can be seen from Table 1, the Ai Qubo Pa inclusion compound capsules, which were included with the gamma-cyclodextrin, had a dissolution end point at pH6.8 phosphate buffer solution (without calcium-containing medium) containing 0.5 wt% SDS, which was substantially identical to a dissolution end point at pH6.8 phosphate buffer solution (with calcium-containing medium) containing 2.78mmol/L calcium chloride and 0.5 wt% SDS. The Ai Qubo Pa after inclusion treatment is described, so that the contact of multivalent metal ions and Ai Qubo Pa can be reduced, the formation of chelate can be effectively reduced, the solubility of Ai Qubo Pa after inclusion can be increased, the dissolution end point of Ai Qubo Pa is improved, the absorption of Ai Qubo Pa medicine is facilitated, the dissolution effect of Ai Qubo Pa can be ensured even if the medicine is taken together with substances containing calcium ions such as food, and meanwhile, the reduction or even ineffectiveness of curative effect caused by improper medicine taking can be avoided, so that the purpose of promoting the normal exertion of the medicine effect of Ai Qubo Pa is achieved, and the flexibility and the compliance of medicine taking of patients are improved.
Example 6
In this example, ai Qubo Pa inclusion compound was prepared by the same preparation method as in example 5, and then tablets were prepared and the same test conditions were carried out, and after dissolving Ai Qubo Pa inclusion compound tablets in a solution of 0.5 wt% SDS in pH6.8 phosphate buffer solution and 2.78mmol/L calcium chloride in a pH6.8 phosphate buffer solution medium containing 0.5 wt% SDS, HPLC test was carried out on each of the two filtrates. The difference is that in this example, ai Qubo Pa clathrate tablet adopts powder direct tabletting method, the clathrate is sieved by a 40-mesh sieve, and mixed with croscarmellose sodium and microcrystalline cellulose for 10min, mannitol for 10min, and magnesium stearate for 5min, and tabletting to obtain Ai Qubo Pa clathrate tablet.
The elution results of this example are shown in Table 1. As can be seen from Table 1, the Ai Qubo Pa inclusion compound tablets included with the gamma-cyclodextrin had a dissolution end point at pH6.8 phosphate buffer solution (without calcium-containing medium) containing 0.5 wt% SDS, which was substantially identical to a dissolution end point at pH6.8 phosphate buffer solution (with calcium-containing medium) containing 2.78mmol/L calcium chloride and 0.5 wt% SDS. The Ai Qubo Pa after inclusion treatment is described, so that the contact of multivalent metal ions and Ai Qubo Pa can be reduced, the formation of chelate can be effectively reduced, the solubility of Ai Qubo Pa after inclusion can be increased, the dissolution end point of Ai Qubo Pa is improved, the absorption of Ai Qubo Pa medicine is facilitated, the dissolution effect of Ai Qubo Pa can be ensured even if the medicine is taken together with substances containing calcium ions such as food, and meanwhile, the reduction or even ineffectiveness of curative effect caused by improper medicine taking can be avoided, so that the purpose of promoting the normal exertion of the medicine effect of Ai Qubo Pa is achieved, and the flexibility and the compliance of medicine taking of patients are improved.
Example 7
Beagle dogs were divided into two groups, one group was fed with the tablets of comparative example 1 on an empty stomach, one group was fed with the tablets of comparative example 1 after feeding, and blood sample was collected at time points of 0.25, 0.5, 1,2, 4, 6, 8, 10, 24, 32, 48, 72 h. Sample injection detection is carried out after the treatment in the following way: 30ul of plasma was taken, 150ul of an internal standard acetonitrile solution was added, the supernatant was taken after centrifugation, and 100ul of a methanol-water (1:1, v/v) mixed solution was added and mixed well.
The granules prepared according to the prescription process of example 5 are respectively filled into enteric capsules and gastric capsules for animal experiments. The administration and sample prescription were the same as those of the tablets prepared in comparative example 1, and the results are shown in Table 2. Comparative example 1 tableting preparation C in fed as compared to fasting conditions max And AUC decreased significantly. .
Summary
The dissolution data of the pharmaceutical compositions of comparative example 1 and examples 1 to 6, which were dissolved in a pH6.8 phosphate buffer solution containing 0.5 wt% SDS, and a pH6.8 phosphate buffer solution medium containing 0.5 wt% SDS containing 2.78mmol/L calcium chloride, are shown in the following table:
TABLE 1 dissolution results in calcium-free Medium for comparative example 1, examples 1-6
Remarks "/" were not examined, and the dissolution percentage (%)
As can be seen from the above table, all of the examples in the medium of phosphate buffer pH6.8 (without calcium medium) containing 0.5 wt% SDS were eluted. Wherein the cumulative dissolution percentage of examples 1-6 reaches more than 90% at 15min, and the dissolution rate is better than that of comparative example 1.
In a phosphate buffer solution (calcium-containing medium) medium of pH6.8 containing 0.5 wt% SDS and containing 2.78mmol/L calcium chloride, the Ai Qubo Pa tablet of comparative example 1 (without cyclodextrin inclusion treatment) had a more remarkable effect of calcium ions on dissolution of comparative example 1 than in examples 1 to 6, a slower dissolution rate, a cumulative dissolution percentage of only 50% for 15min, and a dissolution end point of 64% or less; after inclusion by cyclodextrin, calcium ions have no influence on the dissolution of examples 1-6, and the dissolution end point can reach more than 95%.
Pharmacokinetic data for fasted/fed conditions in beagle dogs are shown in table 2:
TABLE 2
Remarks "/" do not compare
The results are shown in Table 2, and the tabletted preparation of comparative example 1 shows that the beagle dogs C had a higher feeding condition than the fasting condition max And AUC decreased significantly, with food effects evident. Ai Qubo Pa inclusion compound enteric capsule and gastric soluble capsule which are included by cyclodextrin, and C is used for fasted and fed condition of beagle dogs max The difference between the medicine and AUC is very small, which indicates that Ai Qubo Pa after inclusion treatment can be normally absorbed even if taken together with food, thereby ensuring the curative effect of Ai Qubo Pa; is beneficial to reducing the limitation of medication and increasing the flexibility and compliance of the medication of patients.
The inclusion compound provided by the invention can reduce the contact between multivalent metal ions and Ai Qubo Pa, thereby reducing the formation of chelate; and improves the solubility of the medicine. The preparation prepared from the inclusion compound and other pharmaceutically acceptable auxiliary materials can improve the dissolution rate of the medicine, is favorable for the absorption of Ai Qubo Pa medicine, can ensure the dissolution effect of Ai Qubo Pa even if taken together with substances containing calcium ions such as food and the like, and can avoid the reduction or even ineffectiveness of the curative effect caused by improper administration, thereby ensuring the normal exertion of the medicine effect and further improving the flexibility and compliance of the medicine taking of patients. In addition, the preparation method of the Ai Qubo Pa inclusion compound provided by the invention has the advantages of high inclusion rate, low production cost and simple process, and is suitable for industrial production.
In the description of the present specification, a description referring to terms "one embodiment," "some embodiments," "examples," "specific examples," or "some examples," etc., means that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the present invention. In this specification, schematic representations of the above terms are not necessarily directed to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, the different embodiments or examples described in this specification and the features of the different embodiments or examples may be combined and combined by those skilled in the art without contradiction.
While embodiments of the present invention have been shown and described above, it will be understood that the above embodiments are illustrative and not to be construed as limiting the invention, and that variations, modifications, alternatives and variations may be made to the above embodiments by one of ordinary skill in the art within the scope of the invention.
Claims (4)
1. A capsule comprising an inclusion compound of eltrombopag, characterized by comprising Ai Qubo pa or a pharmaceutically acceptable salt thereof, and an inclusion material; the inclusion material is at least one of alpha-cyclodextrin and gamma-cyclodextrin; the capsule is a gastric capsule or an enteric capsule; based on the total weight of the capsule,
ai Qubo Pa content is 12.76 wt%,
the inclusion material content was 47.74 wt%,
the filler content was 30.50 wt%,
the content of disintegrant was 8.00% by weight,
the lubricant content was 1.00 wt.%.
2. The capsule of claim 1, wherein the filler comprises at least one selected from the group consisting of microcrystalline cellulose, powdered cellulose, lactose, pregelatinized starch, lactitol, mannitol, sorbitol, maltodextrin, magnesium aluminum silicate, anhydrous dibasic calcium phosphate, and calcium carbonate; the disintegrating agent comprises at least one selected from corn starch, pregelatinized starch, modified corn starch, croscarmellose sodium, crospovidone, sodium carboxymethyl starch, methylcellulose, microcrystalline cellulose, modified cellulose gum, agar, guar gum, hydroxymethyl cellulose and salts thereof; the lubricant comprises at least one selected from the group consisting of talc, magnesium stearate, stearic acid, colloidal silicon dioxide, mineral oil, wax, sodium stearyl fumarate, glyceryl behenate, polyethylene glycol, and hydrogenated vegetable oil.
3. A method for preparing the capsule according to claim 1, wherein the preparation method of the Ai Qubo pa clathrate comprises at least one selected from the group consisting of a saturated aqueous solution method, a grinding method, an ultrasonic method, a freeze-drying method, a spray-drying method and a reduced pressure drying method.
4. A method according to claim 3, characterized in that the method is a freeze-drying method: weighing the components respectively, completely dissolving the inclusion material in water, adding Ai Qubo Pa or pharmaceutically acceptable salt thereof, stirring, centrifuging, collecting supernatant, and lyophilizing the supernatant to obtain clathrate.
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| CN114099435A (en) * | 2021-12-16 | 2022-03-01 | 南京威凯尔生物医药科技有限公司 | Esprop-pasolamine nano micelle and preparation method thereof |
| CN115166125B (en) * | 2022-08-16 | 2023-07-28 | 郑州大学第一附属医院 | Method for rapidly determining Ai Qubo Pa concentration in human plasma by adopting ultra-high performance liquid chromatography-tandem mass spectrometry |
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| NZ580888A (en) * | 2007-05-03 | 2012-03-30 | Glaxosmithkline Llc | Compositions of eltrombopag olamine substantially free from coordinating metals or reducing sugars |
| CN102697745A (en) * | 2007-05-03 | 2012-10-03 | 葛兰素史密斯克莱有限责任公司 | Novel pharmaceutical composition |
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| Title |
|---|
| 慢性特发性血小板减少性紫癜治疗药物罗米司亭和艾曲波帕;姚远兵等;《中国新药杂志》;20101230(第24期);全文 * |
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