CN114344306B - Pharmaceutical composition containing phenylpyrimidinone hydrochloride, pharmaceutical preparation containing pharmaceutical composition, preparation method and application of pharmaceutical composition - Google Patents
Pharmaceutical composition containing phenylpyrimidinone hydrochloride, pharmaceutical preparation containing pharmaceutical composition, preparation method and application of pharmaceutical composition Download PDFInfo
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Abstract
The invention belongs to the technical field of medicines, and particularly relates to a pharmaceutical composition containing phenylpyrimidinone hydrochloride, a pharmaceutical preparation containing the pharmaceutical composition, and a preparation method and application of the pharmaceutical preparation. In particular, the pharmaceutical compositions of the present invention comprise a compound of formula I-A, and a pharmaceutically acceptable carrier. By particle size modification of the compounds of the formula I-AThe problems of mixing uniformity, content uniformity and slow dissolution are solved by line limitation, auxiliary material composition and dosage screening and preparation process research. The pharmaceutical composition or the pharmaceutical preparation provided by the invention has the characteristics of good content uniformity, good stability, rapid disintegration, capability of realizing rapid dissolution, preparation by adopting two processes of direct mixing or wet granulation, preference for using the direct mixing process, simple prescription process, low cost, energy conservation, environmental protection, easiness in industrial application and the like.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a pharmaceutical composition containing phenylpyrimidinone hydrochloride, a pharmaceutical preparation containing the pharmaceutical composition, a preparation method of the pharmaceutical preparation, and application of the pharmaceutical composition or the pharmaceutical preparation in medicines.
Background
Erectile dysfunction (Erectile Dysfunction, ED), commonly known as "impotence", refers to the persistent inability of men to achieve or maintain penile erection of sufficient rigidity under sexual stimulation to complete satisfactory sexual life, with a course of disease more than 3 months being clinically diagnosed as ED. Epidemiological data (J Androl,2011, 32:496).
In the medicinal treatment of ED, a Phosphodiesterase 5 (PDE 5) inhibitor is convenient, safe and effective to use and is easy to be accepted by most patients, thus being the most preferred medicament in clinic at present. The currently commercially approved oral PDE5 inhibitors for the treatment of erectile dysfunction are: sildenafil (Sildenafil, viagra), vardenafil (Vardenafil, levitra), tadalafil (Tadalafil, cialis) and avanafil (Avanafil, stendra). Wherein sildenafil was developed by the american pyrox company and approved by the us FDA for marketing in 1998, was the first oral drug approved by the us FDA for the treatment of ED. Subsequently in 2003, bayer and glazin smith company joined to release vardenafil and gift company released tadalafil. In 2012, the FDA approved avanafil for marketing.
Since phosphodiesterases have at least 11 enzyme lines and more subtypes, highly selective PDE5 inhibitors are critical in developing therapeutic dysfunctions. Among the four PDE5 inhibitors which are currently marketed, sildenafil and vardenafil have poor selectivity on PDE1 and PDE6, cause side effects such as facial flushing, vision disorder and the like, have potential cardiovascular risks, have shorter half-lives of the two compounds, and are not suitable for long-term administration; the tadalafil has longer half-life period and can be used once a day, but has poor selectivity on PDE11, and side effects of back pain and muscle soreness influence the compliance of patients in the use of medicines; although atorvastatin has low clinical adverse reactions due to high selectivity, the atorvastatin has short half-life and is not suitable for long-term administration. PDE5 inhibitors there is still an unmet clinical need and PDE5 inhibitors with high selectivity and long half-life are the direction of development of new generation PDE inhibitors.
Chinese issued patent publication No. CN102216279B discloses a compound of phenylpyrimidinone and pharmaceutically acceptable salts thereof, which has a high phosphodiesterase 5 (PDE 5) inhibitory activity. The compound takes natural product epimedium flavone as a lead structure, takes analytical data of computational chemistry as a reference, and carries out fine structure fine tuning design and synthesis work through structure modification and splicing synthesis technology, so that a candidate compound with better pharmaceutical comprehensive evaluation cost than sildenafil is finally obtained. From studies of preclinical toxicology, pharmacodynamics, and pharmacokinetic properties, etc., it was found that the phenylpyrimidinone compound has activity (IC 50 =0.62 nM) sildenafil (IC 50 Compared with sildenafil, the preparation method has the advantages of high activity, high selectivity, low toxicity, definite drug effect, simple structure, easiness in synthesis and the like.
Based on animal experimental data of preclinical oral administration, the compound can be developed into an oral solid preparation by oral gastrointestinal administration, and can enhance erectile function by inhibiting PDE5 enzyme activity and increasing intracellular cGMP levels.
However, in the phenylpyrimidinone compound preparation, the phenylpyrimidinone compound occupies a small amount, so that the problem of uniformity of mixing easily occurs in the preparation process, and the problem of slow dissolution of finished products of the preparation easily occurs. Therefore, the preparation of the phenylpyrimidinone-containing pharmaceutical composition or pharmaceutical preparation has the advantages of good content uniformity, good stability, rapid disintegration, realization of rapid dissolution, simple prescription process, low cost, energy conservation and environmental protection, and is a technical problem solved by the invention.
Disclosure of Invention
Problems to be solved by the invention
In view of the above problems, the present invention provides a pharmaceutical composition containing phenylpyrimidinone hydrochloride, a pharmaceutical formulation comprising the same, and a preparation method and use thereof.
Solution for solving the problem
In a first aspect, the present invention provides a pharmaceutical composition comprising a phenylpyrimidinone hydrochloride, comprising a compound of formula I-A, and a pharmaceutically acceptable carrier.
Wherein the particle size D of the compound of formula I-A 90 ≤30μm。
Preferably, the particle size D of the compound of formula I-A 90 ≤20μm。
Preferably, the pharmaceutically acceptable carrier includes fillers, disintegrants, binders and lubricants.
More preferably, the pharmaceutically acceptable carrier consists of a filler, a disintegrant, a binder and a lubricant.
Preferably, the pharmaceutical composition comprises the following components in percentage by weight: 1 to 20 percent of compound of formula I-A, 35 to 90 percent of filling agent, 1 to 20 percent of disintegrating agent, 1 to 20 percent of adhesive and 0.1 to 5 percent of lubricant.
More preferably, the pharmaceutical composition comprises the following components in weight percent: 1 to 10 percent of compound of formula I-A, 72 to 90 percent of filler, 1 to 8 percent of disintegrating agent, 1 to 8 percent of adhesive and 0.5 to 2 percent of lubricant.
Preferably, the filler is at least one of lactose, corn starch, mannitol, sorbitol and microcrystalline cellulose, the disintegrant is at least one of low-substituted hydroxypropyl cellulose, croscarmellose sodium, carboxymethyl starch sodium and crospovidone, the binder is at least one of hydroxypropyl cellulose, hydroxypropyl methylcellulose and povidone, and the lubricant is at least one of magnesium stearate, sodium stearyl fumarate, talc and colloidal silicon dioxide.
More preferably, the filler is lactose and microcrystalline cellulose, the disintegrant is sodium carboxymethyl starch, the binder is povidone, and the lubricant is magnesium stearate.
In a second aspect, the present invention provides a method for preparing the above pharmaceutical composition, comprising the steps of: the compound of formula I-A is admixed with a pharmaceutically acceptable carrier.
In a third aspect, the present invention provides a pharmaceutical formulation made from the pharmaceutical composition described above.
Preferably, the pharmaceutical preparation is a tablet, capsule, granule, pill, powder or dry suspension.
More preferably, the pharmaceutical formulation is a tablet or capsule.
In a fourth aspect, the present invention provides a method for preparing the pharmaceutical formulation described above, optionally by direct mixing, wet granulation or dry granulation, preferably by direct mixing.
The preparation method comprises the following steps:
(1) Pulverizing the compound of formula I-A to a target particle size, sieving filler, disintegrant, binder and lubricant;
(2) Uniformly mixing the crushed compound of the formula I-A in the step (1), the sieved filler, the sieved disintegrating agent and the sieved adhesive to obtain a mixed material; or alternatively
Uniformly mixing the crushed compound of the formula I-A in the step (1), the sieved filler and the sieved disintegrating agent, adding the mixture into the sieved adhesive solution in the step (1), and granulating to obtain medicine-containing granules;
(3) Adding the lubricant sieved in the step (1) into the mixed material or the drug-containing particles in the step (2), and uniformly mixing to obtain total mixed powder;
(4) Tabletting or encapsulating the total mixed powder in the step (3).
Preferably, the filler, disintegrant, binder and lubricant in step (1) are sieved through an 80 mesh sieve.
Preferably, step (4) further comprises a step of coating after tabletting.
In a fifth aspect, the present invention provides the use of a pharmaceutical composition as defined above or a pharmaceutical formulation as defined above for the manufacture of a medicament for the treatment and/or prophylaxis of diseases and/or conditions associated with PDE5 enzymes.
Preferably, the PDE5 enzyme-related disease and/or disorder comprises: erectile dysfunction, pulmonary arterial hypertension, female sexual dysfunction, premature labor, dysmenorrhea, benign prostatic hyperplasia, bladder outlet obstruction, incontinence, unstable and variant angina, hypertension, congestive heart failure, renal failure, atherosclerosis, stroke, peripheral vascular disease, raynaud's disease, inflammatory disease, bronchitis, chronic asthma, allergic rhinitis, glaucoma and intestinal motility disorders.
ADVANTAGEOUS EFFECTS OF INVENTION
The invention provides a pharmaceutical composition containing phenylpyrimidinone hydrochloride, a pharmaceutical preparation containing the pharmaceutical composition, a preparation method and application thereof, and the composition specifically contains a compound shown in a formula I-A and a pharmaceutically acceptable carrier. The problems of mixing uniformity, content uniformity and slow dissolution are solved by limiting the granularity of the compound shown in the formula I-A, combining auxiliary materials, screening the dosage and researching a large amount of preparation process experiments. The pharmaceutical composition or the pharmaceutical preparation provided by the invention has the characteristics of good content uniformity, good stability, rapid disintegration, capability of realizing rapid dissolution, preparation by adopting two processes of direct mixing or wet granulation, preference for using the direct mixing process, simple prescription process, low cost, energy conservation, environmental protection, easiness in industrial application and the like.
Drawings
FIG. 1 shows the XRPD patterns of the compounds of formula I-A (without comminution treatment).
FIG. 2 shows the XRPD pattern for the compound of formula I-A (comminution treatment).
Figure 3 shows the XRPD pattern of the compound of formula I-a (simulated wet granulation).
Detailed Description
[ definition of terms ]
Phenyl pyrimidinone hydrochloride
The phenyl pyrimidinone compound is a compound with a phenyl pyrimidinone structure, and Chinese issued patent with publication number of CN102216279B discloses a phenyl pyrimidinone compound and pharmaceutically acceptable salts thereof, which have higher phosphodiesterase (PDE 5) inhibition activity and better comprehensive evaluation of the pharmacy property than sildenafil. "phenylpyrimidinone hydrochloride" refers to the hydrochloride salt of a phenylpyrimidinone compound.
Compounds of formula I-A
The "compound of formula I-A" is a hydrochloride of a phenylpyrimidinone compound, having the following chemical name: 5, 6-diethyl-2- [ 2-n-propoxy-5- (2- (4-methylpiperazin-1-yl) acetamido) phenyl ] pyrimidin-4 (3H) -one hydrochloride.
Pharmaceutically acceptable carrier
By "pharmaceutically acceptable carrier" is meant a pharmaceutical adjuvant that is compatible with the pharmaceutically active ingredient and not deleterious to the subject, including, but not limited to, fillers, binders, disintegrants, lubricants, wetting agents, thickening agents, glidants, flavoring agents, preservatives, antioxidants, pH adjusting agents, solvents, co-solvents, surfactants, and the like.
[ pharmaceutical composition ]
The invention provides a pharmaceutical composition containing phenylpyrimidinone hydrochloride, which comprises a compound of formula I-A and a pharmaceutically acceptable carrier.
In one embodiment, the particle size D of the compound of formula I-A 90 ≤30μm。
In a preferred embodiment, the particle size D of the compounds of the formula I-A 90 ≤20μm。
In one embodiment, the pharmaceutically acceptable carrier includes fillers, disintegrants, binders and lubricants.
In a preferred embodiment, the pharmaceutically acceptable carrier consists of a filler, a disintegrant, a binder and a lubricant.
In one embodiment, the pharmaceutical composition comprises the following components in weight percent: 1 to 20 percent of compound of formula I-A, 35 to 90 percent of filling agent, 1 to 20 percent of disintegrating agent, 1 to 20 percent of adhesive and 0.1 to 5 percent of lubricant.
In a preferred embodiment, the pharmaceutical composition comprises the following components in weight percent: 1 to 10 percent of compound of formula I-A, 72 to 90 percent of filler, 1 to 8 percent of disintegrating agent, 1 to 8 percent of adhesive and 0.5 to 2 percent of lubricant.
In one embodiment, the filler is at least one of lactose, corn starch, mannitol, sorbitol, and microcrystalline cellulose, the disintegrant is at least one of low substituted hydroxypropyl cellulose, croscarmellose sodium, sodium carboxymethyl starch, and crospovidone, the binder is at least one of hydroxypropyl cellulose, hydroxypropyl methylcellulose, and povidone, and the lubricant is at least one of magnesium stearate, sodium stearyl fumarate, talc, and colloidal silicon dioxide.
In a preferred embodiment, the filler is lactose and microcrystalline cellulose, the disintegrant is sodium carboxymethyl starch, the binder is povidone, and the lubricant is magnesium stearate.
[ method for producing pharmaceutical composition ]
The invention provides a preparation method of the pharmaceutical composition, which comprises the following steps: the compound of formula I-A is admixed with a pharmaceutically acceptable carrier.
[ pharmaceutical preparation ]
The invention provides a pharmaceutical preparation which is prepared from the pharmaceutical composition.
In one embodiment, the pharmaceutical formulation is a tablet, capsule, granule, pill, powder, or dry suspension.
In a preferred embodiment, the pharmaceutical formulation is a tablet or capsule.
[ preparation method of pharmaceutical preparation ]
The invention provides a preparation method of the medicinal preparation, which can be selected from direct mixing, wet granulation or dry granulation, and is preferably a direct mixing preparation method.
The preparation method comprises the following steps:
(1) Pulverizing the compound of formula I-A to a target particle size, sieving filler, disintegrant, binder and lubricant;
(2) Uniformly mixing the crushed compound of the formula I-A in the step (1), the sieved filler, the sieved disintegrating agent and the sieved adhesive to obtain a mixed material; or alternatively
Uniformly mixing the crushed compound of the formula I-A in the step (1), the sieved filler and the sieved disintegrating agent, adding the mixture into the sieved adhesive solution in the step (1), and granulating to obtain medicine-containing granules;
(3) Adding the lubricant sieved in the step (1) into the mixed material or the drug-containing particles in the step (2), and uniformly mixing to obtain total mixed powder;
(4) Tabletting or encapsulating the total mixed powder in the step (3).
In one embodiment, the filler, disintegrant, binder, and lubricant in step (1) are sieved through an 80 mesh screen.
In one embodiment, step (4) further comprises the step of coating after tabletting.
[ medical use ]
The present invention provides the use of the above pharmaceutical composition or the above pharmaceutical formulation for the manufacture of a medicament for the treatment and/or prophylaxis of diseases and/or conditions associated with PDE5 enzymes.
In one embodiment, the PDE5 enzyme-related disease and/or disorder comprises: erectile dysfunction, pulmonary arterial hypertension, female sexual dysfunction, premature labor, dysmenorrhea, benign prostatic hyperplasia, bladder outlet obstruction, incontinence, unstable and variant angina, hypertension, congestive heart failure, renal failure, atherosclerosis, stroke, peripheral vascular disease, raynaud's disease, inflammatory disease, bronchitis, chronic asthma, allergic rhinitis, glaucoma and intestinal motility disorders.
The present invention will be described in further detail by way of examples. It should not be construed that the scope of the above subject matter of the present invention is limited to the following examples. Various substitutions and alterations are also possible, without departing from the spirit of the invention, and are intended to be within the scope of the invention.
The method for detecting evaluation indexes such as disintegration time limit, friability, mixing uniformity, content uniformity, dissolution curve, appearance, powder flowability and the like in the embodiment or the specific example of the invention is as follows:
disintegration time limit: the tablet should disintegrate completely in 900ml water at 37+ -1deg.C within 30min and pass through screen mesh by adopting the disintegration time limit checking method of Chinese pharmacopoeia 2020 edition, if a small amount of tablet floats or adheres to stainless steel tube or screen mesh, but no hard core exists, the tablet can be used as a compliance rule. The repeated measurement of 6 tablets should meet the regulations, and if one tablet does not meet the regulations, 6 tablets should be taken for repeated test, and all the tablets should meet the regulations.
Friability: the tablet friability checking method of Chinese pharmacopoeia 2020 edition, 0923 is adopted, a tablet friability tester is used, a plurality of tablets are taken, the total weight of the tablet is about 6.5g, the powder which is fallen off from the tablet is blown off by a blower, the tablet is precisely weighed and placed in a cylinder, the cylinder is rotated for 100 times, the tablet is taken out, the powder is removed by the same method, the precise weighing is carried out, the weight loss is less than 1%, and the broken, cracked and crushed tablet cannot be detected, and the experiment is generally carried out only once. If the weight loss exceeds 1%, the weight loss should be repeated 2 times, and the average weight loss of 3 times is not more than 1%, and the broken, cracked and crushed pieces cannot be detected.
Mixing uniformity: and (3) adopting a content detection method, taking mixed 10 medicinal powders at different positions, detecting the content, and calculating an RSD value according to a content result, wherein the RSD value is generally less than 5%, and the requirements of mixing uniformity are met.
Content uniformity: and (3) detecting the content by adopting a content detection method, respectively taking single measurement unit material quantity (not less than 10 sampling points), and calculating an A+2.2S value according to a content result, wherein A+2.2<15 is generally considered to meet the requirement of content uniformity.
And (3) dissolving out: the second method of dissolution and release rate measurement of 0931 is adopted in Chinese pharmacopoeia 2020 edition, 0.1mol/L hydrochloric acid solution is adopted as dissolution medium, and sampling time is adopted: 5. 10, 15, 30 and 45min, medium volume 900ml, rotating speed: dissolution was measured at 50rpm, limit requirement: the dissolution rate of 45 minutes should be not less than 80% of the labeled amount.
Appearance of plain tablets: the plain tablets have complete and smooth appearance, uniform color, no sticking and uncovering, proper hardness and wear resistance, so as to avoid abrasion and breakage in the packaging and transportation processes.
Powder flowability: the angle of repose is the maximum angle formed by the free inclined plane and the horizontal plane of the powder accumulation layer, and the smaller the angle of repose, the smaller the friction force, the better the fluidity, and the better the fluidity is considered to be when the angle of repose is less than 30 degrees, and the fluidity requirement in the production process can be met when the angle of repose is less than 40 degrees. At >40 °, the flowability requirements during production are generally not considered to be met.
In order to solve the technical problems of mixing uniformity, content uniformity and the like of small-dose medicaments, the invention screens the dosage of auxiliary materials such as a filling agent, a disintegrating agent, an adhesive and the like and researches a large amount of preparation process experiments, and examines indexes such as mixing uniformity, content uniformity, disintegration time limit, friability, powder fluidity, appearance of tablets and the like of a medicament composition containing phenylpyrimidinone hydrochloride.
All starting materials and reagents are commercially available or prepared by methods conventional in the art, not specifically described in the examples below. Wherein the compound of formula I-A is purchased from Shandong Telman pharmaceutical Co., ltd, lactose (trade name: G200, F100) is purchased from German America Le Wosi Bay milk house company, microcrystalline cellulose (trade name: PH101, PH 102) is purchased from Asahi chemical Co., ltd, sodium carboxymethyl starch (trade name: ZW-SSG-D) is purchased from Huzhou Waring pharmaceutical Co., ltd, povidone (alias: polyvinylpyrrolidone, trade name: K30) is purchased from American Basoff company, starch, magnesium stearate (trade name: SH-YM-M) is purchased from Anhui mountain river pharmaceutical auxiliary stock Co., ltd, film coating premix (trade name: european generation YS-1-7027 CN) is purchased from Shanghai Carekang coating technology Co., ltd, gelatin hollow capsule shell (trade name: 1#, 2) is purchased from Suzhou capsule Co., ltd.
Example 1: tablet prescription (direct tabletting)
The preparation process comprises the following steps:
(1) Pretreatment of materials: pulverizing the compound of formula I-A, and determining particle size D 90 =18.8 μm; sieving the auxiliary materials with 80 mesh sieve for standby.
(2) Weighing: weighing the compound of the formula I-A, lactose, microcrystalline cellulose, carboxymethyl starch sodium, povidone and magnesium stearate according to the prescription amount.
(3) Mixing: the ingredients other than magnesium stearate were added to the hopper mixer at a speed of 10rpm/min and mixed for 10 minutes.
(4) Lubrication: adding magnesium stearate, setting the rotating speed to 10rpm/min, and mixing for 5 minutes to obtain total mixed powder; the mixing uniformity was measured by taking 10 points at different positions of the mixer. The particle content was measured and the tablet weight was calculated.
(5) Tabletting: tabletting by adopting a rotary tablet press, and tabletting a die: a6.5 mm round shallow concave die is used for controlling the hardness range to 40-80N, the weight of the tablet is about 125mg, the weight difference limit is +/-5.0%, sampling is carried out, and friability, content and the like are measured.
(6) Coating: coating powder accounting for 4.0 percent of the single pot loading amount of the tablet cores is weighed by adopting a film coating premix (Opadry YS-1-7027 CN) and added into purified water, and the mixture is stirred and dispersed uniformly to prepare a 15% (w/w) coating solution; the tablet cores are placed in a coating pot, the air inlet temperature is set to be 55-65 ℃, the material temperature is controlled to be 40-60 ℃, the rotating speed of the pot body is set to be 1-10 rpm/min, the coating operation is carried out according to the coating program, and the coating weight gain is controlled to be 1-3%.
Example 2: tablet prescription (Wet granulation)
The preparation process comprises the following steps:
(1) Pretreatment of materials: pulverizing the compound of formula I-A, and determining particle size D 90 =18.8 μm; sieving the auxiliary materials with 80 mesh sieve for standby.
(2) Weighing: weighing the compound of the formula I-A, lactose, microcrystalline cellulose, carboxymethyl starch sodium, povidone and magnesium stearate according to the prescription amount.
(3) Preparing an adhesive solution: the povidone K30 with the prescription dosage is added into 50 percent ethanol solution, and is continuously stirred to prepare clear 5 percent (w/w) povidone ethanol solution for standby.
(3) Premixing: the ingredients other than magnesium stearate were added to the high-speed wet granulator and mixed for 10min with stirring at 180 rpm/min.
(4) Granulating: setting stirring rotation speed of 180rpm/min and shearing rotation speed of 1200rpm/min, adding binder solution for granulating, controlling slurry adding time within 5min, setting stirring rotation speed of 180rpm/min and shearing rotation speed of 2000pm/min after slurry adding is finished, and stirring for 5min.
(5) Wet finishing: wet-granulating the granulated material with a swing granulator (20-mesh screen).
(6) And (3) drying: the wet material is added into a boiling dryer, the air inlet temperature is controlled to be 60 ℃, and the wet material is dried until the moisture content is less than 3.0 percent (measured by a halogen rapid moisture meter, measured at 105 ℃/5 min).
(7) And (3) dry finishing: and (3) drying and granulating the dried material by a crushing granulator (the granulating rotation speed is 1000rpm/min, and the V-shaped screen is 2.0 mm).
(8) Lubrication: adding magnesium stearate, setting the rotating speed to 10rpm/min, and mixing for 5 minutes to obtain total mixed powder; the mixing uniformity was measured by taking 10 points at different positions of the mixer. The particle content was measured and the tablet weight was calculated.
(9) Tabletting: tabletting by adopting a rotary tablet press, and tabletting a die: a6.5 mm circular shallow concave die is used for controlling the hardness range to 40-80N, the weight of the sheet is about 125mg, the weight difference limit is +/-5.0%, sampling is carried out, and friability, content and the like are measured.
(10) Coating: coating powder accounting for 4.0 percent of the single pot loading amount of the tablet cores is weighed by adopting a film coating premix (Opadry YS-1-7027 CN) and added into purified water, and the mixture is stirred and dispersed uniformly to prepare a 15% (w/w) coating solution; the tablet cores are placed in a coating pot, the air inlet temperature is set to be 55-65 ℃, the material temperature is controlled to be 40-60 ℃, the rotating speed of the pot body is set to be 1-10 rpm/min, the coating operation is carried out according to the coating program, and the coating weight gain is controlled to be 1-3%.
Example 3: tablet prescription (direct tabletting)
The preparation process is the same as in example 1.
Example 4: capsule prescription (direct mixing)
The process before capsule filling was the same as in example 1, the capsule filling steps were as follows: filling the capsule filling plate with No. 2 capsules, wherein the average filling weight is about 125mg; and monitoring the product properties and weight differences in the filling process. Capsule properties: white or off-white powder after capsule shell removal; weight difference limit: 5.0%.
Example 5: capsule prescription (Wet granulation)
The process before capsule filling was the same as in example 2, capsule filling: filling the capsule filling plate with No. 2 capsules, wherein the average filling weight is about 125mg; and monitoring the product properties and weight differences in the filling process. Capsule properties: white or off-white powder after capsule shell removal; weight difference limit: 5.0%.
Example 6: capsule prescription (Wet granulation)
The prescription and process design of the example refer to the "example 222 capsule" in paragraphs 973-977 of the specification of the issued patent (issued publication number: CN 102216279B), and the preparation process is as follows: pulverizing the compound of formula I-A, and determining particle size D 90 =18.8 μm; sieving the compound of the formula I-A and auxiliary materials such as starch, lactose and microcrystalline cellulose with an 80-mesh sieve, weighing according to the prescription amount, preparing proper granules by using a 10% polyvinylpyrrolidone ethanol solution as an adhesive, preparing proper granules by using a 16-mesh sieve, drying at 65 ℃, finishing granules by using a 14-mesh sieve, adding magnesium stearate, uniformly mixing, measuring the content of the granules, calculating the loading amount, and filling into capsules (filling with No. 1 capsules, wherein the average filling weight is 198 mg).
Example 7: tablet prescription (Wet granulation)
The prescriptions and process designs of this example refer to the "example 223 tablet (wet granulation method)" in paragraphs 978-980 of the specification of the issued patent (issued bulletin number: CN 102216279B), and the preparation process is as follows: pulverizing the compound of formula I-A, and determining particle size D 90 =18.8 μm; sieving lactose, microcrystalline cellulose and carboxymethyl starch sodium containing compound of formula I-A with 80 mesh sieve, weighing according to prescription, making soft material with 8% starch slurry, granulating with 16 mesh sieve, drying, grading, adding magnesium stearate, mixing, measuring granule content, calculating tablet weight, and tablettingObtained (the tablet is pressed by a round shallow concave die with the thickness of 8.0mm, the hardness range is controlled to be 60-100N, and the average value of the tablet weight is about 200 mg).
Example 8: tablet prescription (direct tabletting)
The preparation process is similar to example 1, except that the disintegrant and binder of example 8 are crospovidone and hydroxypropyl cellulose.
Comparative example 1: tablet prescription (direct tabletting)
The preparation process is the same as in example 1, with the following differences: comparative example 1 Using the uncrushed compound of formula I-A (found: D 90 =88 μm).
Comparative example 2: capsule prescription (Wet granulation)
The preparation process is the same as in example 6, with the following differences: comparative example 2 Using the uncrushed compound of formula I-A (found: D 90 =88 μm).
And (3) detecting a crystal form:
the XRPD patterns of the compound of formula I-a (not milled), the compound of formula I-a (milled), and the crystalline form of the compound of formula I-a (simulated wet granulation, drying after wetting with a small amount of solvent) were determined by X-ray powder diffraction, and are shown in fig. 1, 2, and 3, respectively. From the XRPD crystalline pattern, the compound of formula I-a is stable in crystalline form during the pulverization or simulated wet granulation process, and is not transformed, presumably to have more desirable stability during subsequent formulation.
Evaluation results table 1:
evaluation results table 2:
evaluation results table 3:
note that: in the above 3 evaluation result tables, CR means the cumulative elution amount (cumulated release rate).
Analysis of results:
the specific auxiliary materials are combined in the examples 1-8, and the prepared tablets or capsules have good disintegration effects and can be completely disintegrated within 30 min. The auxiliary material combination of the examples 1-5 has better disintegration effect than that of the examples 6-8, the disintegration can be completely realized within 10min, the examples 1-5 can realize quick dissolution, and the examples 6-8 are slower in dissolution.
The crude drugs used in examples 1-8 were all mechanically pulverized to control the particle size D 90 Less than or equal to 30 μm (measured value is D) 90 =18.8 μm), the prepared material total mixed powder has good mixing uniformity and content uniformity of finished products; comparative examples 1 to 2 used the crude drug without pulverization (found D 90 =88 μm), the material powder flowability, mixing uniformity, and product content uniformity were relatively poor.
The intermediate powder in the two processes of direct mixing and wet granulation in examples 1-5 has the flowability and compressibility meeting the requirements, the disintegration effect and dissolution behavior of each process are almost the same, the difference is small, the weight difference/loading difference, the content and the content uniformity meeting the requirements, the process steps are simple, special production conditions and production equipment are not needed, the cost is low, and the method is suitable for industrial production. The two processes are preferably a direct mixing process, so that the steps of wet granulation, drying, dry granulation and the like are reduced, the operation is simpler and more convenient, the environment protection, energy conservation and emission reduction are facilitated, and the method is more suitable for industrial production.
Claims (9)
1. A pharmaceutical composition comprising a phenylpyrimidinone hydrochloride comprising a compound of formula I-a, and a pharmaceutically acceptable carrier;
wherein the particle size D of the compound of formula I-A 90 Less than or equal to 30 mu m; and the compound of the formula I-A is obtained by mechanical crushing;
the pharmaceutically acceptable carrier comprises a filler, a disintegrant, a binder and a lubricant;
the filler is lactose and microcrystalline cellulose, the disintegrating agent is carboxymethyl starch sodium, the adhesive is povidone, and the lubricant is magnesium stearate;
the pharmaceutical composition comprises the following components in percentage by weight: 1 to 20 percent of compound of formula I-A, 35 to 90 percent of filling agent, 1 to 20 percent of disintegrating agent, 1 to 20 percent of adhesive and 0.1 to 5 percent of lubricant.
2. The pharmaceutical composition comprising phenylpyrimidinone hydrochloride according to claim 1, characterized in that:
particle size D of the compound of formula I-A 90 ≤20μm。
3. The pharmaceutical composition comprising phenylpyrimidinone hydrochloride according to claim 1 or 2, characterized in that:
the pharmaceutical composition comprises the following components in percentage by weight: 1 to 10 percent of compound of formula I-A, 72 to 90 percent of filler, 1 to 8 percent of disintegrating agent, 1 to 8 percent of adhesive and 0.5 to 2 percent of lubricant.
4. A process for the preparation of a pharmaceutical composition comprising phenylpyrimidinone hydrochloride according to any of claims 1 to 3, comprising the steps of: the compound of formula I-A is admixed with a pharmaceutically acceptable carrier.
5. A pharmaceutical formulation made from the phenylpyrimidinone hydrochloride-containing pharmaceutical composition according to any of claims 1-3, which is a tablet, capsule, granule, pill, powder or dry suspension.
6. The pharmaceutical formulation of claim 5, wherein: the pharmaceutical preparation is a tablet or a capsule.
7. A method of preparing a pharmaceutical formulation according to claim 5 or 6, comprising the steps of:
(1) Pulverizing the compound of formula I-A to a target particle size, sieving filler, disintegrant, binder and lubricant;
(2) Uniformly mixing the crushed compound of the formula I-A in the step (1), the sieved filler, the sieved disintegrating agent and the sieved adhesive to obtain a mixed material; or alternatively
Uniformly mixing the crushed compound of the formula I-A in the step (1), the sieved filler and the sieved disintegrating agent, adding the mixture into the sieved adhesive solution in the step (1), and granulating to obtain medicine-containing granules;
(3) Adding the lubricant sieved in the step (1) into the mixed material or the drug-containing particles in the step (2), and uniformly mixing to obtain total mixed powder;
(4) Tabletting or encapsulating the total mixed powder in the step (3).
8. Use of a pharmaceutical composition comprising phenylpyrimidinone hydrochloride according to any of claims 1 to 3 or of a pharmaceutical formulation according to claim 5 or 6 for the preparation of a medicament for the treatment and/or prevention of diseases and/or disorders related to PDE5 enzymes.
9. Use according to claim 8, characterized in that: the diseases and/or conditions associated with PDE5 enzymes include erectile dysfunction, pulmonary arterial hypertension, female sexual dysfunction, premature labor, dysmenorrhea, benign prostatic hyperplasia, bladder outlet obstruction, incontinence, unstable and variant angina, hypertension, congestive heart failure, renal failure, atherosclerosis, stroke, peripheral vascular disease, raynaud's disease, inflammatory diseases, bronchitis, chronic asthma, allergic rhinitis, glaucoma and intestinal motility disorders.
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| CN202210079753.0A CN114344306B (en) | 2022-01-24 | 2022-01-24 | Pharmaceutical composition containing phenylpyrimidinone hydrochloride, pharmaceutical preparation containing pharmaceutical composition, preparation method and application of pharmaceutical composition |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102216279A (en) * | 2008-12-10 | 2011-10-12 | 上海特化医药科技有限公司 | Phenyl pyrimidone compounds, pharmaceutical compositions, preparation methods and uses thereof |
| WO2021208976A1 (en) * | 2020-04-17 | 2021-10-21 | 上海海雁医药科技有限公司 | Solid pharmaceutical preparation, preparation method therefor and use thereof |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102216279A (en) * | 2008-12-10 | 2011-10-12 | 上海特化医药科技有限公司 | Phenyl pyrimidone compounds, pharmaceutical compositions, preparation methods and uses thereof |
| WO2021208976A1 (en) * | 2020-04-17 | 2021-10-21 | 上海海雁医药科技有限公司 | Solid pharmaceutical preparation, preparation method therefor and use thereof |
Non-Patent Citations (1)
| Title |
|---|
| 2017年浙江省春拍中科院上海分院科技成果投资路演推介会;《今日科技》;20170420(第03期);全文 * |
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