CN110946826A - Riociguat oral preparation and preparation method thereof - Google Patents
Riociguat oral preparation and preparation method thereof Download PDFInfo
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Abstract
A riociguat oral preparation and a preparation method thereof relate to the technical field of pharmaceutical preparations, and aim to develop a riociguat oral preparation with good absorption, high bioavailability and higher medication compliance, the oral preparation comprises, by weight, 10-20% of riociguat, 20-35% of an oil phase, 2-18% of an emulsifier and 30-65% of a co-emulsifier, and a preparation method of the oral preparation is also provided, which comprises the following steps: mixing oil phase, emulsifier and co-emulsifier, adding riociguat, homogenizing under high pressure to obtain emulsion, adsorbing the emulsion onto adsorbent by fluidized bed spray drying equipment, coating, and making into capsule or tablet. The riociguat oral preparation can be used as a long-acting, slow-release and efficient medicine for treating pulmonary hypertension.
Description
Technical Field
The invention relates to the technical field of pharmaceutical preparations, in particular to a riociguat oral preparation with good absorption, high bioavailability and higher medication compliance and a preparation method thereof.
Background
Riociguat (riociguat), known by the chemical name N- [4, 6-diamino-2- [1- [ (2-fluorophenyl) methyl ] -1H-pyrazolo [3,4-b ] pyridin-3-yl ] -5-pyrimidinyl ] -N-methylcarbamic acid methyl ester, has a molecular weight of 422.4157. It is a soluble guanylate cyclase activator developed by bayer corporation in germany, is an important signaling enzyme, can be activated by Nitric Oxide (NO) to catalyze the conversion of Guanosine Triphosphate (GTP) into second messenger cyclic guanosine monophosphate (cGMP), is the first drug approved by FDA as the class of drugs for treating pulmonary hypertension and the first drug of any class that shows efficacy for patients with chronic thromboembolic pulmonary hypertension (CTEPH), is also the first and only approved drug in the european union for CTEPH, and riociguat is the salvage of patients with pulmonary hypertension.
Clinical research shows that the riociguat preparation for treating pulmonary hypertension has high curative effect, tolerance, slight untoward effect and absolute bioavailability of 94%, and the oral administration has no influence on the bioavailability caused by food. However, riociguat has extremely poor solubility, slow dissolution rate, low in vitro dissolution rate and unfavorable drug absorption. In order to solve the problem, various oral preparations capable of improving the dissolution rate of the oral preparation are developed at home and abroad, and the oral preparations can be mainly divided into two types according to the preparation process: one is to micronize the riociguat component, foreign tablet with trade name "ademapas" developed by the german bayer company of the riociguat original research pharmaceutical enterprise, domestic preparation for treating pulmonary hypertension as disclosed in chinese patent document CN106913554A, riociguat oral solid preparation as disclosed in chinese patent document CN105596311A, and riociguat oral disintegrating tablet as disclosed in chinese patent document CN105878197A, etc.; the other is prepared by adopting a solid dispersion technology, for example, a solid pharmaceutical preparation containing riociguat disclosed in Chinese patent document CN 104434845A. The above oral preparations can improve the in vitro dissolution of riociguat to a certain extent, but the particle size of the active ingredients of the drug is the key for determining the dissolution, and the particle size of the riociguat drug particles in the oral preparations is only in the micron level, generally 1-10 μm or more, so the in vitro dissolution of the oral preparations is relatively limited.
In addition, riociguat has short half-life in vivo, so the duration of the drug effect is short after oral administration, and the oral preparations do not have the function of long-acting slow release after administration, so that multiple administrations in a short time are required, thereby increasing the administration cost of patients. More importantly, since different people may have different constitutions and in vivo environments, the oral preparation without long-acting slow-release function also has the risk of life safety hazard caused by overhigh blood concentration.
Disclosure of Invention
In view of the above-mentioned shortcomings of the prior art, the present invention is directed to developing a novel riociguat oral preparation, which can substantially increase the dissolution rate of riociguat in vitro to promote absorption and solve the problem of poor solubility, and has a long-acting sustained-release function to reduce the administration frequency and improve the administration safety.
In order to achieve the above object, the inventors provide a riociguat oral preparation comprising a core component consisting of the following components in percentage by weight: 10-20% of riociguat, 20-35% of oil phase, 2-18% of emulsifier and 30-65% of co-emulsifier.
In order to prepare the preparation with the best stability and the best emulsification effect, the riociguat oral preparation provided by the invention preferably comprises a core component consisting of the following components in percentage by weight: 13-19% of riociguat, 25-31% of oil phase, 3-10% of emulsifier and 40-60% of co-emulsifier.
The riociguat oral preparation is a riociguat self-microemulsifying administration system liquid preparation comprising riociguat, oil phase, emulsifier and co-emulsifier. The self-microemulsifying drug delivery system refers to a stable, uniform and isotropic mixture composed of drug, oil, emulsifier and co-emulsifier, and is a lipid binding system. The system is basically characterized in that the system can spontaneously emulsify under gastrointestinal peristalsis to form microemulsion with the particle size of less than 100nm after being taken orally, and the system becomes a research hotspot in the field of medicaments at present. Although self-microemulsifying drug delivery systems are known to those skilled in the art as a new oral formulation for improving the solubility of poorly soluble drugs, promoting oral absorption, and improving bioavailability, the products of the self-microemulsifying drug delivery systems developed at present are very attractive. On one hand, the reason is that the drug molecules can influence the emulsification effect of the self-microemulsifying drug delivery system, different drugs have different influences, and an effective self-microemulsifying system can be formed only by special auxiliary material combinations, so that the types and proportions of oil, emulsifier and co-emulsifier are determined by long-term large-scale experimental screening in combination with the characteristics of the drugs, and the risk of screening failure is extremely high; on the other hand, the self-microemulsifying drug delivery system contains a large amount of surfactant, and the surfactant with high concentration can cause the irritation of the preparation to the human body and even generate toxic and side effects. Due to the special limitation of the properties of riociguat, no pharmaceutical preparation of riociguat self-microemulsifying drug delivery system has been developed so far. The inventor carries out a large amount of long-term systematic scientific experimental researches, overcomes serious difficulties, and finally has a fortunate experiment to prepare the formula of the self-microemulsifying drug delivery system suitable for riociguat with excellent emulsification effect after abandoning the conventional method.
Preferably, in the riociguat oral preparation, the oil phase is at least one selected from soybean oil, ethyl oleate, isopropyl myristate, isopropyl palmitate, stearic acid, vaseline, cottonseed oil, corn oil, sulfated castor oil, caprylic/capric triglyceride, glycerol monooleate, oleic acid, olive oil, peanut oil, almond oil, lard, liquid paraffin, cholesterol, beeswax and spermaceti wax.
More preferably, in the riociguat oral preparation provided by the invention, the oil phase is at least one selected from soybean oil, ethyl oleate, isopropyl myristate, beeswax and vaseline. The oil phase substances have better stability to the preparation and are more beneficial to industrial production.
Preferably, in the riociguat oral preparation provided by the invention, the emulsifier is at least one selected from polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, polyethylene glycol stearate-15, sodium calcium oleate, polyethylene glycol glyceryl oleate, polyethylene glycol octylphenyl ether, caprylic/capric polyethylene glycol glyceride, poloxamer 188, saponin, tween-80, liquid lecithin, micronized magnesium oxide, sucrose laurate, sucrose palmitate, sucrose stearate, polyethylene glycol glyceryl laurate, glycerol polyethylene glycol-75-stearate, carboxymethyl cellulose and casein.
More preferably, in the riociguat oral preparation, the emulsifier is at least one selected from polyoxyethylene castor oil, poloxamer 188, micronized magnesium oxide and casein protease, so that the use of surfactant can be reduced and avoided to the maximum extent.
Preferably, in the above riociguat oral preparation, the co-emulsifier is at least one selected from ethanol, propylene glycol, carboxymethyl cellulose, ethyl cellulose, isopropyl alcohol, urea, 1, 2-propylene glycol, n-butanol, diethylene glycol monoethyl ether, propylene carbonate, lysine, enzyme-treated starch, modified starch and sodium chloride.
More preferably, in the riociguat oral preparation provided by the invention, the co-emulsifier is selected from at least one of ethanol, propylene glycol and sodium chloride, and has the advantages of no toxicity, no harm and no pollution.
In order to overcome the defects of carrying, inconvenient taking, high production cost, low stability and the like of a liquid preparation, the riociguat oral preparation is preferably prepared into a solid dosage form, so the riociguat oral preparation further comprises an adsorbent, and the weight ratio of the adsorbent to a core component is 1:1-3.8: 1.
Preferably, in the riociguat oral preparation provided by the invention, the adsorbent is selected from any one of anhydrous calcium chloride, calcium chloride dihydrate, zinc oxide, zinc hydroxide, anhydrous calcium hydrogen phosphate, calcium carbonate, magnesium oxide micropowder silica gel, microcrystalline cellulose, lactose, aluminum hydroxide gel powder, sodium chloride, pregelatinized starch, sucrose powder, glucose powder, mannitol, sorbitol starch, cyclodextrin, sodium carbonate, sodium bicarbonate, calcium sulfate, povidone, polyethylene glycol 4000, polyethylene glycol 6000, diatomite and glycolide-lactide copolymer which has a molecular weight of 2-4 million and has a multi-layer fold inside to form a net structure.
More preferably, in the riociguat oral preparation provided by the invention, the adsorbent is selected from any one of zinc hydroxide, microcrystalline cellulose, anhydrous calcium hydrogen phosphate and glycolide-lactide copolymer with a molecular weight of 2-4 ten thousand and a multi-layer wrinkled and net-shaped structure inside. The adsorbents have higher drug loading capacity and stronger adsorption capacity to the drugs, can effectively avoid the loss of drug molecules in the subsequent operation process, and are more favorable for spray granulation.
More preferably, in the riociguat oral preparation provided by the invention, the molar ratio of glycolide to lactide in the glycolide-lactide copolymer with the molecular weight of 2-4 ten thousand and the internal multi-layer folds in a net structure is 50: 50-85: 15. Compared with the conventional glycolide-lactide copolymer with the surface only provided with the pore structure, the glycolide-lactide copolymer with the reticular structure remarkably increases the drug loading rate of riociguat, improves the adsorption stability and delays the drug release time.
More preferably, in the riociguat oral preparation provided by the invention, the glycolide-lactide copolymer with the molecular weight of 2-4 ten thousand and the internal multi-layer folds in a net structure is prepared by the following method: dissolving glycolide-lactide copolymer with molecular weight of 2-4 ten thousand in dichloromethane solution, uniformly mixing, dispersing in 0.5% polyvinyl alcohol (w/w) and 10% sodium chloride (w/w) aqueous solution at the speed of 40-60 mL/s, stirring for dispersing, centrifuging, collecting, and drying to obtain the final product.
Preferably, the riociguat oral preparation provided by the invention further comprises a coating layer formed by a biodegradable material, wherein the biodegradable material is selected from any one of glycolide-lactide copolymer with the molecular weight of 8-20 ten thousand, polyvinyl alcohol-glycolide-lactide copolymer with the molecular weight of 8-12 ten thousand molar ratio of 50:50, polylactic acid with the molecular weight of 5-15 ten thousand, collagen, polycaprolactone and gelatin. The biodegradable materials are derived from the same endogenous substances, can be degraded into lactic acid in vivo after being taken, can promote the absorption of gastrointestinal tracts, and has no side effect.
More preferably, in the riociguat oral preparation provided by the invention, the molar ratio of lactide to glycolide in the glycolide-lactide copolymer with the molecular weight of 8-20 ten thousand is 75: 25-100: 0.
Preferably, the riociguat oral preparation provided by the invention further comprises an adhesive material, wherein the adhesive material is carbomer, and the carbomer can swell when meeting water, rapidly increase the volume and be blocked by pylorus, so that the retention time of the medicament in the gastrointestinal tract can be effectively prolonged.
More preferably, in the riociguat oral preparation provided by the invention, the type of the adhesion material carbomer is 934 or 934P.
Preferably, the riociguat oral preparation provided by the invention is a tablet.
The traditional carbomer is of a flocculent or powdery structure, which is not beneficial to tabletting and forming, and more preferably, in the riociguat oral preparation provided by the invention, the carbomer is of a spherical structure with the particle size of 2-30 mu m, the spherical structure is beneficial to uniform mixing and dispersion and forming and pressing of tablets, and the special particle size can generate uniform pore size for the tablets and does not influence the release of riociguat molecules.
Preferably, the riociguat oral preparation provided by the invention further comprises a lubricant, wherein the weight ratio of the lubricant to the core component is 1:80-1: 90.
more preferably, in the riociguat oral preparation provided by the invention, the lubricant is at least one selected from magnesium stearate, stearic acid, calcium stearate and sodium stearyl fumarate.
More preferably, in the riociguat oral preparation, the lubricant is sodium stearyl fumarate or stearic acid, and the two lubricants are water-soluble lubricants, so that the forming and the compression of tablets are facilitated.
In addition, the invention also provides a preparation method of the riociguat oral preparation, which comprises the following steps:
1) weighing the oil phase, the emulsifier and the coemulsifier according to the prescription amount, uniformly mixing, adding the riociguat according to the prescription amount, and treating by a high-pressure homogenizer to obtain a riociguat self-microemulsifying liquid preparation;
2) weighing a prescription amount of adsorbent, and uniformly adsorbing the riociguat self-microemulsifying liquid preparation obtained in the step 1) with the adsorbent by adopting fluidized bed spray drying equipment to obtain an riociguat pellet;
3) weighing a formula amount of biodegradable material, and dissolving with at least one solvent of ethyl acetate, dichloromethane, acetone and dimethyl sulfoxide to obtain a coating solution;
4) uniformly spraying the coating solution obtained in the step 3) on the surface of the riociguat pellet obtained in the step 2) by adopting fluidized bed spray drying equipment to form a coating layer, thus obtaining the riociguat coated pellet;
5) weighing the adhesion material with the prescription amount, uniformly mixing the adhesion material with the riociguat coated pellet obtained in the step 4), and filling the mixture into a capsule shell to obtain the riociguat sustained-release capsule; or respectively weighing the adhesion material and the lubricant in the prescription amount, uniformly mixing the adhesion material and the lubricant with the riociguat coated pellet obtained in the step 4), and tabletting by using a tabletting machine to obtain the riociguat sustained-release tablet.
Has the advantages that:
compared with the prior art, the invention has the following advantages:
1. the invention develops the riociguat self-microemulsifying drug delivery system for the first time, the system has excellent emulsification effect, can be rapidly dispersed and spontaneously emulsified in vivo after being taken orally to form micro-emulsion droplets with the particle size of 1-30 nm, and is reduced by three orders of magnitude compared with the particle size of micron-sized drug molecules of the existing riociguat oral preparation, so that the solubility and the bioavailability of the riociguat are greatly improved;
2. the riociguat oral preparation provided by the invention greatly reduces or even avoids the use of a surfactant, and overcomes the defects of stimulation to human bodies and toxic and side effects caused by high concentration of the surfactant in the traditional self-microemulsifying drug delivery system.
3. The riociguat oral preparation provided by the invention realizes the slow release effect of riociguat molecules by adopting three measures of a special adsorbent (glycolide-lactide copolymer with a multi-layer fold net-shaped structure inside), a special coating layer formed by a biodegradable material and pressing into a tablet to reduce the specific surface area, effectively inhibits the burst effect, improves the administration safety, simultaneously prolongs the residence time of the riociguat molecules in the stomach and intestine by combining the application of a sticky material carbomer, finally realizes the long-acting slow release effect of the riociguat oral preparation, shortens the administration period from once a day to once a three days in the prior art, and improves the treatment effect and the compliance of medication;
4. the preparation method of the riociguat oral preparation provided by the invention is simple and easy to implement, the equipment is simple and easy to operate, special instruments or equipment are not required, the cost is low, and the preparation method is energy-saving and environment-friendly.
Drawings
FIG. 1 is an electron micrograph of carbomer 934P, an adhesive material used in the riociguat oral formulation provided by the present invention;
FIG. 2 is an electron microscope image of the glycolide-lactide copolymer as the adsorbent used in the riociguat oral preparation provided by the present invention;
FIG. 3 is a graph showing the in vitro release profile of riociguat oral formulation provided by the present invention;
figure 4 is a pharmacokinetic plasma concentration-time curve from bioavailability assay.
Detailed Description
The present invention will be described in further detail with reference to specific examples and drawings, which are illustrative of the present invention and are not to be construed as being limited thereto.
The raw materials and reagents used in the following examples are commercially available products unless otherwise specified.
The carbomer used in the following examples is commercially available carbomer of type 934P, which is reprocessed by the inventors and has a spherical structure with a particle size of 2-30 μm, and is shown in FIG. 1 in a scanning electron microscope image of TM4000 type under vacuum.
The glycolide-lactide copolymer (hereinafter referred to as "reticulated glycolide-lactide copolymer") having a molecular weight of 4 ten thousand and a network structure with multiple folds inside, which was used in the following examples, was prepared by the following method: firstly, dissolving a commercially available glycolide-lactide copolymer with a molecular weight of 4 ten thousand mol ratio of 50:50 in a dichloromethane solution, uniformly mixing, dispersing in polyvinyl alcohol with a mass concentration of 0.5% and a sodium chloride solution with a mass concentration of 10% by using an injection pump at a speed of 50mL/s, stirring for 3 hours at 2000rpm by using a self-made mechanical stirring paddle, centrifugally collecting, and drying to obtain the glycolide-lactide-co-polymer composite material, wherein the electron microscope picture of the composite material is shown in figure 2.
Example 1
The formulation of riociguat oral formulation provided in this example is as follows:
example 2
The formulation of riociguat oral formulation provided in this example is as follows:
| riociguat | 10g |
| Vaseline | 20g |
| Casein protease | 7g |
| Ethanol | 35g |
| Zinc hydroxide | 95g |
| Polylactic acid having a molecular weight of 10 ten thousand | 5g |
| Magnesium stearate | 0.9g |
| Carbomer | 20g |
Example 3
The formulation of riociguat oral formulation provided in this example is as follows:
example 4
The formulation of riociguat oral formulation provided in this example is as follows:
| riociguat | 10g |
| Oleic acid ethyl ester | 16g |
| Casein protease | 10g |
| Sodium chloride | 30g |
| Reticulated glycolide-lactide copolymer | 110g |
| Polycaprolactone | 15g |
| Calcium stearate | 0.8g |
| Carbomer | 20g |
Example 5
The formulation of riociguat oral formulation provided in this example is as follows:
| riociguat | 10g |
| Myristic acid isopropyl ester | 20g |
| Polyoxyethylene Castor oil | 7g |
| Sodium chloride | 35g |
| Reticulated glycolide-lactide copolymer | 95g |
| Gelatin | 5g |
| Stearic acid sodium fumarate | 0.9g |
| Carbomer | 20g |
Example 6
The formulation of riociguat oral formulation provided in this example is as follows:
example 7
The formulation of riociguat oral formulation provided in this example is as follows:
| riociguat | 10g |
| Myristic acid isopropyl ester | 20g |
| Polyoxyethylene Castor oil | 7g |
| Sodium chloride | 35g |
| Microcrystalline cellulose | 95g |
| Gelatin | 5g |
| Stearic acid sodium fumarate | 0.9g |
| Carbomer | 20g |
Example 8
The formulation of riociguat oral formulation provided in this example is as follows:
example 9
The formulation of riociguat oral formulation provided in this example is as follows:
example 10
The formula of the above examples 1-9 was prepared into riociguat sustained release tablets according to the following preparation method.
1) Weighing the oil phase, the emulsifier and the coemulsifier (if any) in the prescription amount in a penicillin bottle, uniformly mixing to obtain a clarified liquid, adding the riociguat in the prescription amount, and treating for 2-3min by a high-pressure homogenizer at 500 bar and 700bar to obtain the riociguat self-microemulsion;
2) weighing a prescription amount of adsorbent, and uniformly adsorbing the riociguat self-microemulsion obtained in the step 1) on the adsorbent by adopting fluidized bed spray drying equipment to obtain an riociguat pellet;
3) preparing a coating solution, ① glycolide-lactide copolymer coating solution, weighing 8 ten thousand glycolide-lactide copolymer with the molecular weight of the formula according to a molar ratio of 75:25, dissolving the glycolide-lactide copolymer with ethyl acetate to prepare a solution with the weight ratio of 2%, ② polyvinyl alcohol-glycolide-lactide copolymer coating solution, weighing 7-13 ten thousand polyvinyl alcohol-glycolide copolymer with the molecular weight of 50:50 according to the formula according to the molecular weight of the formula, dissolving the polyvinyl alcohol-glycolide-lactide copolymer with dichloromethane to prepare a solution with the weight ratio of 2%, ③ polylactic acid coating solution, weighing 10 ten thousand polylactic acid with the molecular weight of the formula according to the molecular weight of the formula, dissolving the polylactic acid with ethyl acetate to prepare a solution with the molecular weight of 1.5%, weighing 7 ten thousand polylactic acid with the molecular weight of the formula according to the molecular weight of ④ polycaprolactone coating solution, dissolving the polylactic acid with dichloromethane to prepare a solution with the molecular weight of 1.5%, weighing ⑤ gelatin coating solution, dissolving gelatin with the molecular weight of the formula according to the hot water to prepare a solution with.
4) Uniformly spraying the coating solution obtained in the step 3) on the surface of the riociguat pellet obtained in the step 2) by adopting fluidized bed spray drying equipment, and drying at the temperature of 50 ℃ to form a coating layer, thus obtaining the riociguat coated pellet;
5) respectively weighing the adhesion material and the lubricant in the prescription amount, uniformly mixing the adhesion material and the lubricant with the riociguat coated pellet obtained in the step 4), and tabletting by a tabletting machine to obtain the riociguat sustained-release tablet.
Comparative analysis experiment
1. In vitro Release assay
The riociguat sustained release tablets prepared in example 3, example 8 and example 9 were taken respectively, and the release degree was examined by using a shaker at 37 + -0.1 deg.C, 80ml of water as a release medium and 50 rpm. 5ml of the dissolution liquid is respectively taken and filtered, the subsequent filtrate is taken as a test sample, and 5ml of buffer solution with the same temperature is supplemented in the dissolution cup. According to high performance liquid chromatography (appendix IVA), 20. mu.l of the sample solution was measured precisely at a wavelength of 210nm and injected into a high performance liquid chromatograph to measure the absorbance. Precisely weighing 1.25mg of riociguat reference substance, placing in a 50ml measuring flask, adding mobile phase to dissolve and dilute to scale, and shaking; precisely measuring 1ml, placing into a 20ml measuring flask, adding mobile phase to dilute to scale, shaking, and using as reference solution for determination by the same method. The release amount of each tablet at different time is respectively calculated, and the release amount of each tablet at 1h, 6h, 12h, 24h, 36h, 48h, 60h and 72h is respectively 5-15% of the marked amount at 1h, 25-40% of 12h, 40-65% of 36h and more than 80% of 60h, and all the release amounts meet the requirements. The release time (h) is plotted on the abscissa, and the degree of release (%) is plotted on the ordinate. The results are shown in fig. 3, and after the preferred formulation, example 3 meets the quality control requirements and the release is in compliance with the regulations as compared to examples 8 and 9.
2. Bioavailability assay
Test subjects: 10 rabbits were fasted overnight (free water) with a body weight of 2.5-3 kg. Randomly assigned 2 for blank comparison, and the remaining 8 were randomly divided into two groups of 4 each with half of males and females.
The administration mode comprises the following steps: clamping the body of the rabbit between two legs, holding two ears of the rabbit with a left hand, fixing the head, and grasping forelimbs with a right hand; other experimenters put the mouth gag transversely in the mouth of the rabbit, pressed their tongue under the mouth gag, fixed the mouth gag, grasped the tablet with forceps, delivered to their pharynx from the mouth gag hole, and taken with water. The first group orally administers the riociguat sustained-release tablets (self-developing preparation) prepared in example 1 at 0.03mg/kg in one administration; the second group was orally administered Riociguat film-coated tablets (reference formulation) manufactured by commercial Germany company at 0.03mg/kg three times per day.
Plasma determination: selecting healthy rabbits with weight of 2.5kg, taking 1.5ml of blank blood from ear veins of the rabbits, orally taking a self-development agent half tablet or a reference preparation half tablet for the rabbits, taking the self-development agent half tablet or the reference preparation half tablet with 20ml of warm water, taking blood from the ear veins for 5min, 15min, 30min, 1h, 2h, 4h, 6h, 8h, 12h, 18h, 24h, 36h and 48h, placing the blood in a test tube of heparin anticoagulant, centrifuging at 3000r/min for 10min, and separating plasma. The plasma was treated and the absorbance at 210nm was measured, the results are shown in table 1, and the data obtained was processed using the pharmacokinetic software DAS, and the plasma concentration-time curve is shown in fig. 4.
TABLE 1 pharmacokinetic parameters
And (4) conclusion: the data show that the riociguat oral preparation provided by the invention has higher bioavailability than the riociguat film-coated tablet produced by the commercial Germany company after the same dosage of the medicine is given, the drug effect period is prolonged, and the sustained-release effect is realized.
3. Comparison of sample drug loadings for different adsorbents
Appropriate amounts of the samples of comparative example 5, example 6 and example 7 were dissolved in the mobile phase in the in vitro release rate measurement, and the contents were measured by liquid chromatography conditions for in vitro release rate measurement. The results are as follows.
TABLE 2 drug loading comparison
| Sample (I) | Example 5 | Example 6 | Example 7 |
| Drug loading (%) | 5.02 | 1.12 | 4.61 |
| Encapsulation efficiency (%) | 96.9 | 36.7 | 89.0 |
4. Examination of self-emulsification Effect
Respectively weighing the oil phase of the soybean oil, the micronized magnesium oxide and the propylene glycol as co-emulsifiers, placing the oil phase, the micronized magnesium oxide and the propylene glycol in the same penicillin bottle, uniformly mixing to obtain a clarified liquid, adding the riociguat with the prescription amount, and treating the mixture for 2 to 3min at 500 bar and 700bar by using a high-pressure homogenizer to obtain the riociguat self-microemulsion. 1g of the self-microemulsion was added dropwise to 5ml of water and the nanoemulsion was stirred for 1 minute. The effect of different formulation ratios was examined.
TABLE 3 comparison of the self-emulsifying effects of different formulations
Claims (10)
1. The riociguat oral preparation is characterized by comprising a core component consisting of the following components in percentage by weight: 10-20% of riociguat, 20-35% of oil phase, 2-18% of emulsifier and 30-65% of co-emulsifier.
2. The riociguat oral formulation according to claim 1, wherein: the oral preparation also comprises an adsorbent, and the weight ratio of the adsorbent to the core component is 1:1-3.8: 1.
3. The riociguat oral formulation according to claim 2, wherein: the riociguat oral preparation also comprises a coating layer formed by biodegradable materials, wherein the biodegradable materials are selected from any one of glycolide-lactide copolymer with the molecular weight of 8-20 ten thousand, polyvinyl alcohol-glycolide-lactide copolymer with the molecular weight of 8-12 ten thousand molar ratio of 50:50, polylactic acid with the molecular weight of 5-15 ten thousand, ossein, polycaprolactone and gelatin.
4. The riociguat oral formulation according to claim 3, wherein: the riociguat oral preparation also comprises an adhesion material, wherein the adhesion material is carbomer.
5. The riociguat oral formulation according to claim 4, wherein: the riociguat oral preparation is a tablet, and the carbomer is in a spherical structure with the particle size of 2-30 mu m.
6. The riociguat oral formulation according to claim 5, wherein: the riociguat oral preparation also comprises a lubricant, wherein the weight ratio of the lubricant to the core component is 1:80-1: 90.
7. The riociguat oral formulation according to any one of claims 1 to 6 wherein: the oil phase is selected from at least one of soybean oil, ethyl oleate, isopropyl myristate, isopropyl palmitate, stearic acid, vaseline, sesame oil, cottonseed oil, corn oil, sulfated castor oil, caprylic/capric triglyceride, glyceryl monooleate, oleic acid, olive oil, peanut oil, almond oil, lard, liquid paraffin, cholesterol, beeswax and spermaceti; the emulsifier is selected from at least one of polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, polyethylene glycol stearate-15, sodium calcium oleate, polyethylene glycol octyl phenyl ether, caprylic/capric polyethylene glycol glyceride, poloxamer 188, saponin, tween-80, liquid lecithin, micronized magnesium oxide, sucrose laurate, sucrose palmitate, sucrose stearate, polyethylene glycol laurate, glycerol polyethylene glycol-75-stearate, carboxymethyl cellulose and casein; the coemulsifier is at least one selected from ethanol, propylene glycol, polyethylene glycol 200, polyethylene glycol 400, isopropanol, urea, 1, 2-propylene glycol, n-butanol, diethylene glycol monoethyl ether, propylene carbonate, lysine, triethanolamine and meglumine.
8. The riociguat oral formulation according to any one of claims 2 to 6 wherein: the adsorbent is selected from any one of anhydrous calcium chloride, calcium chloride dihydrate, zinc oxide, zinc hydroxide, anhydrous calcium hydrogen phosphate, calcium carbonate, magnesium oxide micropowder silica gel, microcrystalline cellulose, lactose, aluminum hydroxide gel powder, sodium chloride, pregelatinized starch, sucrose powder, glucose powder, mannitol, sorbitol starch, cyclodextrin, sodium carbonate, sodium bicarbonate, calcium sulfate, povidone, polyethylene glycol 4000, polyethylene glycol 6000, diatomite and glycolide-lactide copolymer with molecular weight of 2-4 ten thousand and multi-layer folds inside to form a net structure.
9. The riociguat oral preparation according to claim 8, wherein the glycolide-lactide copolymer having a molecular weight of 2-4 ten thousand and a network structure with multiple folds inside is prepared by the following method: dissolving glycolide-lactide copolymer with molecular weight of 2-4 ten thousand in dichloromethane solution, uniformly mixing, dispersing in polyvinyl alcohol with mass concentration of 0.5% and sodium chloride solution with mass concentration of 10% at the speed of 50mL/s, stirring for dispersion, filtering, collecting and drying to obtain the final product.
10. The process for preparing an oral formulation of riociguat as claimed in claim 6, comprising the steps of:
1) weighing the oil phase, the emulsifier and the coemulsifier according to the prescription amount, uniformly mixing, adding the riociguat according to the prescription amount, and treating by a high-pressure homogenizer to obtain a riociguat self-microemulsifying liquid preparation;
2) weighing a prescription amount of adsorbent, and uniformly adsorbing the riociguat self-microemulsifying liquid preparation obtained in the step 1) with the adsorbent by adopting fluidized bed spray drying equipment to obtain a riociguat pellet;
3) weighing a formula amount of biodegradable material, and dissolving with at least one solvent of ethyl acetate, dichloromethane, acetone and dimethyl sulfoxide to obtain a coating solution;
4) uniformly spraying the coating solution obtained in the step 3) on the surface of the riociguat pellet obtained in the step 2) by adopting fluidized bed spray drying equipment to form a coating layer, thus obtaining the riociguat coated pellet;
5) respectively weighing the adhesion material and the lubricant in the prescription amount, uniformly mixing the adhesion material and the lubricant with the riociguat coated pellet obtained in the step 4), and tabletting by a tabletting machine to obtain the riociguat sustained-release tablet.
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