CN115990140A - Nafil compound freeze-dried tablet and preparation method thereof - Google Patents
Nafil compound freeze-dried tablet and preparation method thereof Download PDFInfo
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- CN115990140A CN115990140A CN202310117875.9A CN202310117875A CN115990140A CN 115990140 A CN115990140 A CN 115990140A CN 202310117875 A CN202310117875 A CN 202310117875A CN 115990140 A CN115990140 A CN 115990140A
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- temperature
- nafil
- compound
- cyclodextrin
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- 238000002360 preparation method Methods 0.000 title claims abstract description 53
- 150000001875 compounds Chemical class 0.000 title claims abstract description 50
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- 238000000034 method Methods 0.000 claims abstract description 21
- 239000002904 solvent Substances 0.000 claims abstract description 17
- 239000000546 pharmaceutical excipient Substances 0.000 claims abstract description 15
- 239000007884 disintegrant Substances 0.000 claims abstract description 10
- 239000011230 binding agent Substances 0.000 claims abstract description 8
- 238000004108 freeze drying Methods 0.000 claims abstract description 6
- 238000005516 engineering process Methods 0.000 claims abstract description 5
- 150000003839 salts Chemical class 0.000 claims abstract description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 60
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- 235000011852 gelatine desserts Nutrition 0.000 claims description 32
- 239000011780 sodium chloride Substances 0.000 claims description 30
- 239000000243 solution Substances 0.000 claims description 28
- 239000007788 liquid Substances 0.000 claims description 27
- ODLHGICHYURWBS-LKONHMLTSA-N trappsol cyclo Chemical compound CC(O)COC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)COCC(O)C)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1COCC(C)O ODLHGICHYURWBS-LKONHMLTSA-N 0.000 claims description 24
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- BNRNXUUZRGQAQC-UHFFFAOYSA-N sildenafil Chemical compound CCCC1=NN(C)C(C(N2)=O)=C1N=C2C(C(=CC=1)OCC)=CC=1S(=O)(=O)N1CCN(C)CC1 BNRNXUUZRGQAQC-UHFFFAOYSA-N 0.000 claims description 14
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- 125000004528 pyrimidin-5-yl group Chemical group N1=CN=CC(=C1)* 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 210000003079 salivary gland Anatomy 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 230000001568 sexual effect Effects 0.000 description 1
- 229960002639 sildenafil citrate Drugs 0.000 description 1
- DEIYFTQMQPDXOT-UHFFFAOYSA-N sildenafil citrate Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O.CCCC1=NN(C)C(C(N2)=O)=C1N=C2C(C(=CC=1)OCC)=CC=1S(=O)(=O)N1CCN(C)CC1 DEIYFTQMQPDXOT-UHFFFAOYSA-N 0.000 description 1
- 235000019614 sour taste Nutrition 0.000 description 1
- 230000003068 static effect Effects 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000007939 sustained release tablet Substances 0.000 description 1
- 230000009747 swallowing Effects 0.000 description 1
- 235000019605 sweet taste sensations Nutrition 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000000870 ultraviolet spectroscopy Methods 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 238000011179 visual inspection Methods 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Landscapes
- Medicinal Preparation (AREA)
Abstract
The invention relates to a freeze-dried tablet of a nafil compound and a preparation method thereof, belonging to the field of pharmaceutical preparations. The nafil compound freeze-dried tablet is a freeze-dried oral preparation, and comprises the following components: a nafil compound or a pharmaceutically acceptable salt thereof, a solubilizer for clathrating the nafil compound, an excipient, a disintegrant, and a binder; the preparation method comprises the steps of solubilizing the nafil compound by an inclusion technology, and then preparing a freeze-dried oral preparation by adopting a freeze-drying method. The nafil freeze-dried oral preparation prepared by the invention has good formability, quick re-dissolution and good taste, can be rapidly disintegrated in the oral cavity of a patient without water, and has good product stability.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to an alidenafil freeze-dried tablet and a preparation method thereof.
Background
Sildenafil is a phosphodiesterase 5 (pde 5) inhibitor for the treatment of male Erectile Dysfunction (ED). Sildenafil citrate with chemical name 1- [ 3- (6, 7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo [4,3-d ] pyrimidin-5-yl) -4-ethoxybenzenesulfonyl ] -cis-3, 5-dimethylpiperazine citrate (c 23H32n6 os c6H8o 7) with chemical structure:
the solubility of the alidenafil citrate changes along with the change of pH in the physiological pH range, the pH is increased, and the solubility is reduced. The solubility in hydrochloric acid solution at pH 1.2 is high and the solubility in phosphate buffer at pH6.8 is very low. The current common preparation of alidenafil citrate is an oral tablet. The oral cavity is a complex microecological environment, saliva in the oral cavity is mucus secreted by salivary glands, the saliva is colorless and odorless, the pH value is 6.6-7.1 (the normal range is 6.2-7.6), and the daily secretion of normal people is about 1.0-1.5 liters. Human saliva contains, in addition to 99% water, salivary amylase, mucopolysaccharide, mucin, lysozyme, sodium, potassium, calcium, etc.
Freeze-dried orally disintegrating tablets (lyophilized orally disintegrating tablets, LODT) have unique formulation advantages: the disintegration speed is faster, and a stable framework structure is formed in the pre-freezing process, so that the original framework structure is basically unchanged after moisture is removed by vacuum drying. The finished product is loose and porous like a sponge, has obvious pores, can be rapidly disintegrated in the oral cavity, has good re-solubility, and can be disintegrated within 20 seconds or even 5 seconds. The formulation profile translates into unique clinical advantages: can realize the water-free swallowing, is more suitable for patients with dysphagia or refusal to take medicine, especially for mental patients who are easy to spit medicine and Tibetan medicine, and children who are easy to chok medicine and reject medicine. Meanwhile, as the medicine can be swallowed without water, the secret property of taking by a user is increased, and the compliance is improved.
However, there are several difficulties in the preparation of freeze-dried orally disintegrating tablets: firstly, the freeze-drying orally disintegrating tablet has lower drug loading rate; the main drug property is strictly required, and the ideal drug has no bad smell, low solubility and good stability; secondly, the tablet has loose and porous structure, can be rapidly disintegrated, but has poorer mechanical strength, and the product is not easy to form; because the product is mostly in an amorphous state, the product has strong hygroscopicity and poor long-term stability; the product is easy to form gritty feeling in the oral cavity and has poor taste.
In addition, the oral tablet is absorbed through the gastrointestinal tract, so that the bioavailability is low due to the first pass effect of the liver, for example, the conventional tablet of alinafil needs to be taken with water, the peak time after disintegration and oral administration is about 1-3 hours, the peak time is long, the control effect cannot be achieved in a very short time, and the tablet usually needs to be taken about 1 hour before sexual activity, so that a plurality of inconveniences are brought to patients, and the compliance of the patients is poor.
Therefore, from the viewpoint of meeting clinical medication requirements of patients, a new preparation method of oral freeze-dried preparations of the nafil compounds needs to be developed, and meanwhile, the problems of drug loading quantity, reconstitution, long-term stability and difficult product forming are solved, for example, a new oral preparation for quick release and absorption of the african compounds is prepared.
Disclosure of Invention
In the process of developing nafil, such as the freeze-dried oral preparation of alinafil, the applicant finds that the development of the preparation has several difficulties after previous prescription search: first, the increase in drug loading is very difficult; secondly, as the consumption of the adhesive increases, the re-dissolution time of the product is prolonged, and the index requirement of quick re-dissolution cannot be met; thirdly, along with the adjustment of the prescription, the re-dissolution time is accelerated, but the stability of the medicine can not reach the standard, and the impurity exceeds the standard; fourth, the mechanical strength of the product is poor, and the product is not easy to mold.
In order to solve the problems existing in the prior art, the purpose of the present disclosure is to provide a preparation method of a nafil compound preparation, which adjusts contradictions of sample loading quantity, re-dissolution, long-term stability and difficult product forming by a preparation process of inclusion and a strategy of adding a disintegrating agent in a prescription, and the prepared nafil compound preparation, such as an aidenafil freeze-dried oral preparation, has good forming property, fast re-dissolution, good taste, quick disintegration in the oral cavity of a patient without water and good product stability.
In order to achieve the above object, the present disclosure adopts the following specific schemes:
in one aspect, the present disclosure provides a lyophilized oral formulation of nafil comprising the following components: a nafil compound or a pharmaceutically acceptable salt thereof, a solubilizer for clathrating the nafil compound, an excipient, a disintegrant and a binder.
In another aspect, the present disclosure provides a method of preparing a lyophilized oral formulation of the aforementioned nafil-type compound, comprising the steps of:
1) Preparation of liquid medicine
Adding gelatin into water at 40-70 ℃ and stirring to dissolve to prepare solution A; preferably the water temperature is 60 ℃; preferably, the water is purified water;
adding a solubilizer into water to dissolve, adding a nafil compound, stirring to clathrate, and controlling the temperature to be 10-60 ℃, preferably the solution temperature to be 50 ℃; then adding excipient, correctant and disintegrating agent, stirring to dissolve to obtain solution B; preferably, the water is purified water;
mixing the solution A and the solution B to obtain a liquid medicine C; preferably mixing and stirring to obtain a solution C;
2) Injection molding
Standing the liquid medicine C in the step 1, and degassing; preferably, the degassing is carried out with ultrasound; preferably, the degassed liquid medicine is respectively poured into each aluminum foil blister mould;
3) Quick-freezing
Quick-freezing the degassed liquid medicine C by adopting a liquid nitrogen spraying technology, wherein the temperature of the environment is preferably controlled to be between minus 120 ℃ and minus 60 ℃, and the temperature is preferably controlled to be minus 80 ℃;
4) Freeze-drying
Placing the quick-frozen liquid medicine C at-20 ℃, vacuumizing, and preserving heat for 1-3 hours when the vacuum degree is below 10-20 Pa; preferably, the vacuum degree is controlled at 10Pa, and the heat preservation time is 2 hours;
raising the temperature to-10 ℃ to 0 ℃ and keeping the temperature for 0.5 to 5 hours; preferably controlling the temperature at-10 ℃ and keeping the temperature for 2 hours;
raising the temperature to 0-10 ℃ and keeping the temperature for 0.5-5 hours; preferably controlling the temperature at 5 ℃ and keeping the temperature for 2 hours;
raising the temperature to 10-20 ℃ and keeping the temperature for 0.5-5 hours; preferably controlling the temperature at 15 ℃ and keeping the temperature for 2 hours;
raising the temperature to 20-40 ℃, and preserving the heat for 0.5-5 hours; preferably controlling the temperature at 30 ℃ and keeping the temperature for 2 hours;
preferably, the preparation method further comprises step 5) packaging;
preferably, the rotary dehumidifier unit is used for controlling the ambient humidity to be lower than 20% RH, and aluminum foil is adopted for quick heat-sealing packaging.
In another aspect, the present disclosure provides the use of the aforementioned formulation or the method in the manufacture of a medicament for the treatment of male Erectile Dysfunction (ED).
The effective effects obtained by the present disclosure are at least as follows:
1. according to the preparation method of the nafil freeze-dried oral preparation, the nafil compound and the cyclodextrin are prepared into the inclusion compound, so that the solubility of the nafil compound is greatly improved, and the drug loading rate of the freeze-dried oral preparation is further improved;
2. the preparation method of the nafil freeze-dried oral preparation provided by the disclosure can well promote the re-dissolution of the product and improve the stability of the product by using sodium chloride or potassium chloride as a disintegrating agent in the prescription process. Moreover, the use of sodium chloride or potassium chloride in lyophilized oral formulations is not disclosed in the prior art. The mechanism of action of sodium chloride or potassium chloride as a disintegrant is presumed to be: the sodium chloride or potassium chloride molecules which are uniformly dispersed can absorb water rapidly in the pore channel of the freeze-dried orally disintegrating tablet, so that the rapid disintegration of the freeze-dried orally disintegrating tablet is promoted.
3. The nafil freeze-dried oral preparation provided by the disclosure can be rapidly released and absorbed, has the advantages of rapid onset time, good taste, rapid disintegration in the oral cavity of a patient without water, and good product stability.
Detailed Description
In this disclosure, unless otherwise indicated, scientific and technical terms used herein have the meanings commonly understood by one of ordinary skill in the art. Also, the relevant terms and laboratory procedures used herein are terms and conventional procedures widely used in the fields of pharmaceutical preparations, pharmaceutical analysis, chemical drug synthesis. Meanwhile, in order to better understand the present disclosure, definitions and explanations of related terms are provided below.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. The terminology used in the description of the present disclosure is for the purpose of describing particular embodiments only and is not intended to be limiting of the disclosure.
The terms "comprising" and "having" and any variations thereof, are intended to cover a non-exclusive inclusion. For example, a process, method, apparatus, article, or device that comprises a list of steps is not limited to the elements or modules listed but may alternatively include additional steps not listed or inherent to such process, method, article, or device.
References to "a plurality" in this disclosure refer to two or more. "and/or", describes an association relationship of an association object, and indicates that there may be three relationships, for example, a and/or B, and may indicate: a exists alone, A and B exist together, and B exists alone. The character "/" generally indicates that the context-dependent object is an "or" relationship. Meanwhile, for better understanding of the present disclosure, the following definitions and explanations of the related terms are provided.
The term "disintegrant" as used in the present disclosure refers to a substance that rapidly breaks up tablets into fine particles in gastrointestinal fluids, thereby allowing rapid dissolution and absorption of functional ingredients to function. Such materials mostly have good water absorption and expansibility, thereby achieving disintegration of the tablet. In addition to sustained release tablets and tablets of some special uses, disintegrating agents should be added to the general tablets.
The term "inclusion" as used in this disclosure refers to the inclusion of one molecule into the cavity structure of another molecule, the resulting material being referred to as an inclusion compound, which is composed of two compounds: one is a compound that traps other compounds in the structural backbone cavity, called inclusion agent or host molecule; the other is a compound trapped in the inclusion agent structure cavity or pore canal, called an inclusion agent or guest molecule.
In one aspect, the present disclosure provides a lyophilized oral formulation of nafil comprising the following components: a nafil compound or a pharmaceutically acceptable salt thereof, a solubilizer for clathrating the nafil compound, an excipient, a disintegrant and a binder.
In some embodiments of the present disclosure, the disintegrant is selected from one or more of the following: sodium chloride and potassium chloride; sodium chloride is preferred.
In some embodiments of the present disclosure, the solubilizing agent is used to include that class of compounds.
In some embodiments of the present disclosure, the nafil-like compound is 10 to 60 parts by weight, the solubilizing agent is 20 to 100 parts by weight, the excipient is 0 to 30 parts by weight, the disintegrant is 0 to 2 parts by weight, and the binder is 0 to 10 parts by weight;
preferably, the nafil compound is 20 to 40 weight parts, the solubilizer is 30 to 60 weight parts, the excipient is 2 to 10 weight parts, the disintegrating agent is 0.1 to 1 weight part, and the adhesive is 2 to 6 weight parts;
more preferably, the weight parts of the nafil compound, the solubilizer, the excipient, the disintegrating agent and the adhesive are respectively 20, 50, 5, 0.5 and 3.
In some embodiments of the present disclosure, the solubilizing agent is selected from one or more of the following: hydroxypropyl-beta-cyclodextrin, glucosyl-beta-cyclodextrin, maltosyl-beta-cyclodextrin, sodium sulfobutyl-beta-cyclodextrin, (2, 6-dimethyl) -beta-cyclodextrin, beta-cyclodextrin; preferably, hydroxypropyl- β -cyclodextrin or (2, 6-dimethyl) - β -cyclodextrin; more preferably hydroxypropyl-beta-cyclodextrin.
In some embodiments of the present disclosure, the binder is selected from one or more of the following: gelatin, pullulan, xanthan gum; preferably, the gelatin is a pharmaceutically acceptable gelatin or a hydrolyzed gelatin, more preferably a pharmaceutically acceptable gelatin.
In some embodiments of the present disclosure, the components further comprise a flavoring agent that is a sweetener and/or a different flavoring essence, wherein the sweetener is selected from one or more of the following: stevioside, aspartame, sucralose; the essence is selected from one or more of the following: milk-flavored essence, chocolate-flavored essence, orange-flavored essence, and strawberry-flavored essence.
In some embodiments of the present disclosure, the excipient is selected from one or more of the following: mannitol, xylitol, sorbitol, maltitol, lactitol, erythritol, xylose, galactose, trehalose, dextrin, glycine.
In some embodiments of the present disclosure, the nafil-like compound is selected from one of the following: sildenafil, vardenafil, tadalafil.
In some embodiments of the present disclosure, the lyophilized oral formulation comprises the following components: 20mg of alidenafil (calculated as alidenafil), 3mg of gelatin, 5mg of mannitol, 50mg of hydroxypropyl-beta-cyclodextrin, 0.06mg of sucralose and 0.50mg of sodium chloride.
In another aspect, the present disclosure provides a method of preparing a lyophilized oral formulation of the aforementioned nafil-type compound, comprising the steps of:
1) Preparation of liquid medicine
Adding gelatin into water at 40-70 ℃ and stirring to dissolve to prepare solution A; preferably the water temperature is 60 ℃; preferably, the water is purified water;
adding a solubilizer into water to dissolve, adding a nafil compound, stirring to clathrate, and controlling the temperature to be 10-60 ℃, preferably the solution temperature to be 50 ℃; then adding excipient, correctant and disintegrating agent, stirring to dissolve to obtain solution B; preferably, the water is purified water;
mixing the solution A and the solution B to obtain a liquid medicine C; preferably mixing and stirring to obtain a solution C;
2) Injection molding
Standing the liquid medicine C in the step 1, and degassing; preferably, the degassing is carried out with ultrasound; preferably, the degassed liquid medicine is respectively poured into each aluminum foil blister mould;
3) Quick-freezing
Quick-freezing the degassed liquid medicine C by adopting a liquid nitrogen spraying technology, wherein the temperature of the environment is preferably controlled to be between minus 120 ℃ and minus 60 ℃, and the temperature is preferably controlled to be minus 80 ℃;
4) Freeze-drying
Placing the quick-frozen liquid medicine C at-20 ℃, vacuumizing, and preserving heat for 1-3 hours when the vacuum degree is below 10-20 Pa; preferably, the vacuum degree is controlled at 10Pa, and the heat preservation time is 2 hours;
raising the temperature to-10 ℃ to 0 ℃ and keeping the temperature for 0.5 to 5 hours; preferably controlling the temperature at-10 ℃ and keeping the temperature for 2 hours;
raising the temperature to 0-10 ℃ and keeping the temperature for 0.5-5 hours; preferably controlling the temperature at 5 ℃ and keeping the temperature for 2 hours;
raising the temperature to 10-20 ℃ and keeping the temperature for 0.5-5 hours; preferably controlling the temperature at 15 ℃ and keeping the temperature for 2 hours;
raising the temperature to 20-40 ℃, and preserving the heat for 0.5-5 hours; preferably controlling the temperature at 30 ℃ and keeping the temperature for 2 hours;
preferably, the preparation method further comprises step 5) packaging;
preferably, the rotary dehumidifier unit is used for controlling the ambient humidity to be lower than 20% RH, and aluminum foil is adopted for quick heat-sealing packaging.
In some embodiments of the present disclosure, the lyophilized oral formulation is capable of complete dissolution in simulated saliva at 37±1 ℃ for 30 seconds and release of that class of compound.
In another aspect, the present disclosure provides the use of the foregoing formulation or the method of any one of claims 11-12 in the manufacture of a medicament for the treatment of male Erectile Dysfunction (ED).
Examples
For the purpose of making the objects, technical solutions and advantages of the embodiments of the present invention more clear, the technical solutions in the embodiments of the present invention will be clearly and completely described below, and it is apparent that the described embodiments are some embodiments of the present invention, but not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
The raw materials and auxiliary materials used in the following examples were commercially available unless otherwise specified.
Example 1
Preparing inclusion compound: preparing an alidenafil (2, 6-dimethyl) -beta-cyclodextrin, alidenafil hydroxypropyl-beta-cyclodextrin and alidenafil sulfobutyl-beta-cyclodextrin inclusion compound, and determining the content of alidenafil (active pharmaceutical ingredient, active pharmaceutical ingredient, API) in the inclusion compound, wherein the specific operation is as follows: and adding excessive alidenafil into cyclodextrin solutions with different concentrations at 50 ℃, stirring to perform inclusion, filtering after the inclusion reaction reaches equilibrium, and measuring the content of crude drugs in the inclusion compound. Solubility detection data corresponding to inclusion material concentrations for different samples are shown in table 1.
TABLE 1 preparation of clathrate
As is clear from the above table, the solubilization effect of various cyclodextrins was DM-beta-CD < SBECD < HP-beta-CD, with hydroxypropyl-beta-cyclodextrin being the most effective for the solubilization of Aldenafil.
Example 2
The present example provides a prescription composition for preparing an alinafil freeze-dried tablet and a preparation method thereof, and the specific prescription composition is shown in table 2.
Table 2 example 2 prescription composition
| Composition of the components | Prescription quantity |
| Aidinafil (loving danafil meter) | 20mg |
| Gelatin | 3mg |
| Mannitol (mannitol) | 5mg |
| Hydroxypropyl-beta-cyclodextrin | 50mg |
| Sucralose | 0.06mg |
| Sodium chloride | 0.50mg |
| Purifying water to | 0.5mL |
1. Experimental procedure
1.1 preparation of liquid medicine
Weighing 50mL of purified water in a container, setting the temperature to 60 ℃, adding the prescribed amount of medicinal gelatin, stirring and dissolving to obtain a solution A; in addition, 400mL of purified water is measured and placed in a container, the temperature is set to 50 ℃, the prescribed amount of hydroxypropyl-beta-cyclodextrin is added, the prescription amount of alidenafil is added after stirring and dissolving, stirring is carried out to form inclusion, and then mannitol, sucralose and sodium chloride are added and stirring and dissolving are carried out to obtain solution B; mixing the solution A and the solution B, stirring uniformly, adding water to a volume of 500mL, and obtaining a liquid medicine C.
1.2 injection Molding
Standing the liquid medicine C in the step 1, and degassing by adopting ultrasonic waves; and pouring the degassed liquid medicine into each aluminum foil bubble cap mould respectively.
1.3 quick freezing
And (3) quick freezing by adopting a liquid nitrogen spraying technology and controlling the ambient temperature to be minus 80 ℃.
1.4 lyophilization
Cooling the freeze dryer to-20deg.C, placing the mold containing the medicinal liquid into the freeze dryer, vacuumizing, and maintaining the temperature for 2 hr when the vacuum degree is below 10 Pa;
raising the temperature of the shelf to-10 ℃ and keeping the shelf for 2 hours;
raising the temperature of the shelf to 5 ℃ and keeping the shelf for 2 hours;
raising the temperature of the shelf to 15 ℃ and keeping the shelf for 2 hours;
the shelf temperature was raised to 30℃and incubated for 2 hours.
1.5 packaging
And controlling the environmental humidity by using a rotary dehumidifier unit, and carrying out quick heat-sealing packaging by using aluminum foil under the condition of being lower than 20% RH.
Examples 3 to 8
The preparation process is the same as in example 2, and the specific component amounts are shown in Table 3 below.
Examples 3-8 provide lyophilized oral formulations of different prescription compositions. Wherein different amounts of hydroxypropyl-beta-cyclodextrin are prescribed in examples 3 and 4; different gelatin dosages were prescribed in examples 5 and 6; the formulations for different amounts of sodium chloride are given in examples 7 and 8. The method comprises the following steps:
table 3 different prescription compositions of examples 3-8
Examples 9 to 11
Examples 9-11 provide lyophilized oral formulations of sildenafil, tadalafil, vardenafil.
The preparation process is the same as in example 2, and the specific component amounts are shown in Table 4 below.
Table 4 prescription composition of the formulations of examples 9-11
Comparative example 1
The composition of the freeze-dried oral preparation of alidenafil without sodium chloride is shown in table 5, and the preparation method is the same as that of example 2.
Table 5 prescription composition of comparative example 1
| Composition of the composition | Prescription quantity |
| Aidinafil (loving danafil meter) | 20mg |
| Gelatin | 3mg |
| Mannitol (mannitol) | 5mg |
| Hydroxypropyl-beta-cyclodextrin | 50mg |
| Sucralose | 0.06mg |
| Purifying water to | 0.5mL |
Test example 1
The freeze-dried oral preparations prepared in the formulas of examples 2 to 8 and the freeze-dried oral preparation prepared in the formula of comparative example 1 were evaluated for properties, moisture, reconstitution time, content, taste and in-vivo disintegration time. Wherein examples 3, 4 and comparative example 1 were selected to evaluate the performance of the finished formulation based on the amount of hydroxypropyl-beta-cyclodextrin used; examples 2, 5 and 6 the properties of the finished formulations were evaluated based on the selection of the gelatin dosage; examples 2, 7, 8 and comparative example 1 the properties of the finished formulations were evaluated based on the sodium chloride usage selection.
1. Each performance evaluation criterion
Traits: visual inspection was performed to see if the appearance was good and if the pick was easy to extract.
Moisture content: the measurement was carried out by the Fischer-Tropsch method (Chinese pharmacopoeia 2020 edition, fourth edition general rule 0832).
And (3) redissolving time: the reconstitution was performed with 0.5mL of purified water and the reconstitution time was recorded.
Content of active ingredients: ultraviolet-visible spectrophotometry (China pharmacopoeia 2020 edition general rule 0401) is used for measuring absorption value at 292 nm.
Mouthfeel and in vivo disintegration time limit: 10 volunteers were selected, and the drug was put in the mouth without taking with water, and the time limit of disintegration of the drug and whether the subject felt bitter or gritty or good sour and sweet taste during the administration period were recorded.
2. Test results
Examples 3, 4 and comparative example 1 the properties of the finished formulations were evaluated based on the amount of hydroxypropyl-beta-cyclodextrin selection, the specific prescription composition is shown in table 6 and the quality evaluation results are shown in table 7. As is clear from Table 7, when the amount of hydroxypropyl-cyclodextrin was 30mg (example 4), the product was slightly bitter and had a long reconstitution and disintegration time; when the dosage is 70mg (example 3), the taste is moderate, and the re-dissolution and disintegration time are faster. With the reduction of the dosage of the hydroxypropyl-beta-cyclodextrin, the re-dissolution and disintegration time is increased, and the bitter taste is increased to some extent, which indicates that the hydroxypropyl-beta-cyclodextrin not only can be solubilized by inclusion, but also can play the roles of taste masking and disintegrating agent.
TABLE 6 selection of the amount of hydroxypropyl-beta-cyclodextrin-composition of the prescription
TABLE 7 selection of the amount of hydroxypropyl-cyclodextrin-quality assessment
Examples 2, 5 and 6 the properties of the finished formulations were evaluated based on the selection of the gelatin dosage, the specific prescription composition is shown in table 8 and the quality evaluation results are shown in table 9. As can be seen from Table 9, examples 2, 5 and 6 show that the amount of gelatin used affects the properties of the samples, the reconstitution and disintegration times. When the dosage of gelatin is too small, the sample is redissolved and disintegrated quickly, but the property is poor, and the sample is taken up and broken; when the dosage of gelatin is large, the sample has good properties, but the re-dissolution and disintegration time is long; when the dosage of gelatin is 3mg, the quality is good, and the re-dissolution and disintegration time is quicker.
TABLE 8 selection of gelatin dosage-formulation composition
| Composition of the composition | Example 2 | Example 5 | Example 6 |
| Aidenafil | 20mg | 20mg | 20mg |
| Gelatin | 3mg | 5mg | 1mg |
| Mannitol (mannitol) | 5mg | 5mg | 5mg |
| Hydroxypropyl-beta-cyclodextrin | 50mg | 50mg | 50mg |
| Sucralose | 0.06mg | 0.06mg | 0.06mg |
| Sodium chloride | 0.50mg | 0.50mg | 0.50mg |
| Purifying water to | 0.5mL | 0.5mL | 0.5mL |
TABLE 9 selection of gelatin dosage-quality evaluation
Examples 2, 7, 8 and comparative example 1 the properties of the finished formulations were evaluated based on the sodium chloride usage selection, the specific prescription composition is shown in table 10, and the quality evaluation results are shown in table 11. As is clear from Table 11, the amounts of sodium chloride used in comparative example 1, examples 8, 2 and 7 were 0mg, 0.20mg, 0.50mg and 0.80mg, respectively, and as the amount of sodium chloride used was increased, the disintegration and reconstitution times of the product were decreased, but too much amount could affect the taste. When the prescription amount of sodium chloride is 0.50mg, the good taste of the sample and rapid redissolution and disintegration can be ensured, and meanwhile, the content of the effective components is maintained to be 99.9 percent.
In summary, the samples prepared in example 2 and example 3 were good in all detection indexes in day 0.
Table 10 sodium chloride dosage selection-prescription composition
| Composition of the composition | Example 2 | Example 7 | Example 8 | Comparative example 1 |
| Aidenafil | 20mg | 20mg | 20mg | 20mg |
| Gelatin | 3mg | 3mg | 3mg | 3mg |
| Mannitol (mannitol) | 5mg | 5mg | 5mg | 5mg |
| Hydroxypropyl-beta-cyclodextrin | 50mg | 50mg | 50mg | 50mg |
| Sucralose | 0.06mg | 0.06mg | 0.06mg | 0.06mg |
| Sodium chloride | 0.50mg | 0.80mg | 0.20mg | / |
| Purifying water to | 0.5mL | 0.5mL | 0.5mL | 0.5mL |
TABLE 11 sodium chloride dosage selection-quality assessment
Test example 2 stability evaluation
Samples for rapid reconstitution and disintegration can be prepared in both example 2 and example 3, so the freeze-dried oral formulations prepared in example 2, example 3 and comparative example 1 without sodium chloride were subjected to an accelerated stability test in a constant temperature and humidity cabinet for 6 months.
1. Test conditions
The temperature is 40+/-2 ℃, the relative humidity is 75+/-5 percent (RH), and the samples are taken at 0, 3 and 6 months respectively, and the properties, the reconstitution time, the moisture, the content, the in-vivo disintegration time limit and the relative substances are detected, and the stability is compared.
The single impurity structure in the related substances is as follows:
4-ethoxy-3- [ 1-methyl-7 ]Oxo-radicals-3-propyl-6, 7-dihydro-1H-pyrazol (4-3-D) pyrimidin-5-yl]Benzenesulfonic acid
The test results are shown in Table 12.
Table 12 stability test results
2. Test results
As can be seen from table 12, in the accelerated stability test, the dissolution time and the in-oral disintegration time of comparative example 1, in which sodium chloride was not prescribed, were increased in example 2 as compared with comparative example 1; in example 2, the reconstitution and disintegration time of example 3 were unchanged from example 3, but the moisture and related substances increased. Meanwhile, example 2 can significantly improve the stability and reconstitution time of the alidenafil lyophilized tablet.
Thus, when the prescription composition is: 20mg of alidenafil (calculated as alidenafil), 3mg of gelatin, 5mg of mannitol, 50mg of hydroxypropyl-beta-cyclodextrin, 0.06mg of sucralose and 0.50mg of sodium chloride, and the prepared alidenafil freeze-dried oral preparation not only ensures good re-dissolution of the product, but also ensures the long-term stability of the product. The problems of poor drug loading capacity, long redissolution and disintegration time and poor stability of the freeze-dried oral preparation are obviously improved.
Test example 3
The lyophilized oral formulations of examples 9-11 were subjected to an accelerated stability test for 6 months.
1. Test conditions
The temperature is 40+/-2 ℃, the relative humidity is 75+/-5 percent (RH), the samples are taken at 0, 3 and 6 months respectively, and the properties, the reconstitution time, the moisture, the content, the in vivo disintegration time limit and the related substances are detected to examine the stability. The specific test results are shown in Table 13.
TABLE 13 accelerated stability test results
2. Test results
As shown in Table 13, similar to Aidenafil, the sildenafil, tadalafil and vardenafil freeze-dried oral preparation prepared by the invention is placed for 6 months under the acceleration condition, various detection indexes have no obvious change compared with 0 day, and the preparation can be quickly redissolved and disintegrated, and has good stability.
Test example 4 solubility investigation
The freeze-dried oral preparation needs to be rapidly disintegrated in the oral cavity to release the medicine, a static test tube method is adopted for disintegration time limit inspection, glass tubes (with the diameter of 1.5 cm) are opened at two ends, a 20-mesh screen is encapsulated at one end, tablets are put into a 25mL measuring cylinder, 2mL of artificial saliva with the pH of 6.8 at 37+/-1 ℃ is added, the mixture is stood, the time for completely dissolving the sample is recorded, and the disintegration time is required to be controlled at 30 seconds.
Example 2, where the disclosure works best, example 3, where different amounts of hydroxypropyl-beta-cyclodextrin are prescribed; example 5 with different gelatin dosage prescriptions; example 7 of a prescription with different amounts of sodium chloride; examples 9-11 containing lyophilized oral formulations of different nafil-type compounds (including sildenafil, tadalafil, vardenafil); and comparative example 1 of the freeze-dried oral preparation of alidenafil which is the same as the method of the present invention but does not contain sodium chloride, solubility experiments were performed using the above examples and comparative examples, and disintegration times thereof were detected, with the following results:
TABLE 14 disintegration time
| Disintegration time(s) | |
| Example 2 | 4 |
| Example 3 | 10 |
| Example 5 | 27 |
| Example 7 | 4 |
| Example 9 | 6 |
| Example 10 | 4 |
| Example 11 | 7 |
| Comparative example 1 | 39 |
Analysis of results:
in the embodiment 2 with the best effect, the sample of the prescription has the shortest disintegration time, the disintegration time is only 4s, the disintegration time is obviously lower than 30s, and the solubility is obviously improved.
Example 3 for different dosage prescriptions of hydroxypropyl-beta-cyclodextrin; example 7 of a prescription with different amounts of sodium chloride; examples 9-11 containing lyophilized oral formulations of different nafil-type compounds (including sildenafil, tadalafil, vardenafil); the freeze-dried oral preparation prepared by the embodiment has smaller disintegration time, is controlled within 4-10 s, and is far superior to the requirement within the limit of 30s. Example 5, formulated with different gelatin dosages, had a disintegration time of 27s, although slightly higher than that of the presently disclosed optimal example 2, which was still below the limit standard of 30s.
In contrast, the freeze-dried oral preparation of alinafil which is the same as the preparation method but does not contain sodium chloride is adopted in the comparative example 1, the disintegration time is obviously prolonged to 39s, the release of the alinafil compound which is taken as the active ingredient of the medicine is slow and is far higher than the requirement within the limit of 30s, the requirement of fast dissolution is not met, and the qualified freeze-dried oral preparation cannot be prepared.
The above embodiments are only for illustrating the technical solution of the present invention, and are not limiting; although the invention has been described in detail with reference to the foregoing embodiments, it will be understood by those of ordinary skill in the art that: the technical scheme described in the foregoing embodiments can be modified or some technical features thereof can be replaced by equivalents; such modifications and substitutions do not depart from the spirit and scope of the technical solutions of the embodiments of the present invention.
Claims (13)
1. A lyophilized oral formulation of nafil comprising the following components: a nafil compound or a pharmaceutically acceptable salt thereof, a solubilizer for clathrating the nafil compound, an excipient, a disintegrant and a binder.
2. The lyophilized oral formulation of claim 1, wherein the disintegrant is selected from one or more of the following: sodium chloride and potassium chloride; sodium chloride is preferred.
3. The lyophilized oral formulation of claim 1, wherein the solubilizing agent is used to include a nafil-like compound.
4. A lyophilized oral preparation according to any one of claims 1-3, wherein the nafil compound is 10-60 parts by weight, the solubilizer is 20-100 parts by weight, the excipient is 0-30 parts by weight, the disintegrant is 0-2 parts by weight, and the binder is 0-10 parts by weight;
preferably, the nafil compound is 20 to 40 weight parts, the solubilizer is 30 to 60 weight parts, the excipient is 2 to 10 weight parts, the disintegrating agent is 0.1 to 1 weight part, and the adhesive is 2 to 6 weight parts;
more preferably, the weight parts of the nafil compound, the solubilizer, the excipient, the disintegrating agent and the adhesive are respectively 20, 50, 5, 0.5 and 3.
5. The lyophilized oral formulation of any one of claims 1-4, wherein the solubilizing agent is selected from one or more of the following: hydroxypropyl-beta-cyclodextrin, glucosyl-beta-cyclodextrin, maltosyl-beta-cyclodextrin, sodium sulfobutyl-beta-cyclodextrin, (2, 6-dimethyl) -beta-cyclodextrin, beta-cyclodextrin; preferably, hydroxypropyl- β -cyclodextrin or (2, 6-dimethyl) - β -cyclodextrin; more preferably hydroxypropyl-beta-cyclodextrin.
6. The lyophilized oral formulation of any one of claims 1-5, wherein the binder is selected from one or more of the following: gelatin, pullulan, xanthan gum; preferably, the gelatin is a pharmaceutically acceptable gelatin or a hydrolyzed gelatin, more preferably a pharmaceutically acceptable gelatin.
7. The lyophilized oral formulation of any one of claims 1-6, wherein the components further comprise a flavoring agent that is a sweetener and/or a different flavoring essence, wherein the sweetener is selected from one or more of the following: stevioside, aspartame, sucralose; the essence is selected from one or more of the following: milk-flavored essence, chocolate-flavored essence, orange-flavored essence, and strawberry-flavored essence.
8. The lyophilized oral formulation of any one of claims 1-7, wherein the excipient is selected from one or more of the following: mannitol, xylitol, sorbitol, maltitol, lactitol, erythritol, xylose, galactose, trehalose, dextrin, glycine.
9. The lyophilized oral formulation of any one of claims 1-8, wherein the nafil-like compound is selected from one of the following: sildenafil, vardenafil, tadalafil.
10. The lyophilized oral formulation according to any one of claims 1-9, comprising the following components: 20mg of alidenafil (calculated as alidenafil), 3mg of gelatin, 5mg of mannitol, 50mg of hydroxypropyl-beta-cyclodextrin, 0.06mg of sucralose and 0.50mg of sodium chloride.
11. A process for the preparation of a lyophilized oral formulation of a nafil-type compound according to any one of claims 1-10, comprising the steps of:
1) Preparation of liquid medicine
Adding gelatin into water at 40-70 ℃ and stirring to dissolve to prepare solution A; preferably the water temperature is 60 ℃; preferably, the water is purified water;
adding a solubilizer into water to dissolve, adding a nafil compound, stirring to clathrate, and controlling the temperature to be 10-60 ℃, preferably the solution temperature to be 50 ℃; then adding excipient, correctant and disintegrating agent, stirring to dissolve to obtain solution B; preferably, the water is purified water;
mixing the solution A and the solution B to obtain a liquid medicine C; preferably mixing and stirring to obtain a solution C;
2) Injection molding
Standing the liquid medicine C in the step 1, and degassing; preferably, the degassing is carried out with ultrasound; preferably, the degassed liquid medicine is respectively poured into each aluminum foil blister mould;
3) Quick-freezing
Quick-freezing the degassed liquid medicine C by adopting a liquid nitrogen spraying technology, wherein the temperature of the environment is preferably controlled to be between minus 120 ℃ and minus 60 ℃, and the temperature is preferably controlled to be minus 80 ℃;
4) Freeze-drying
Placing the quick-frozen liquid medicine C at-20 ℃, vacuumizing, and preserving heat for 1-3 hours when the vacuum degree is below 10-20 Pa; preferably, the vacuum degree is controlled at 10Pa, and the heat preservation time is 2 hours;
raising the temperature to-10 ℃ to 0 ℃ and keeping the temperature for 0.5 to 5 hours; preferably controlling the temperature at-10 ℃ and keeping the temperature for 2 hours;
raising the temperature to 0-10 ℃ and keeping the temperature for 0.5-5 hours; preferably controlling the temperature at 5 ℃ and keeping the temperature for 2 hours;
raising the temperature to 10-20 ℃ and keeping the temperature for 0.5-5 hours; preferably controlling the temperature at 15 ℃ and keeping the temperature for 2 hours;
raising the temperature to 20-40 ℃, and preserving the heat for 0.5-5 hours; preferably controlling the temperature at 30 ℃ and keeping the temperature for 2 hours;
preferably, the preparation method further comprises step 5) packaging;
preferably, the rotary dehumidifier unit is used for controlling the ambient humidity to be lower than 20% RH, and aluminum foil is adopted for quick heat-sealing packaging.
12. The method of claim 11, wherein the lyophilized oral formulation is completely soluble in simulated saliva at 37±1 ℃ for 30 seconds and releases the nafil-like compound.
13. Use of a formulation according to any one of claims 1-10 or a method according to any one of claims 11-12 in the manufacture of a medicament for the treatment of male Erectile Dysfunction (ED).
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011030351A2 (en) * | 2009-09-03 | 2011-03-17 | Rubicon Research Private Limited | Taste - masked pharmaceutical compositions |
| WO2013123623A1 (en) * | 2012-02-24 | 2013-08-29 | 量子高科（北京）研究院有限公司 | Oroally disintegrating tablet and preparation method therefor |
| US20150250791A1 (en) * | 2014-03-06 | 2015-09-10 | Bhaskara Rao Jasti | Combining sildenafil with caffeine in an oral disintegrating dosage form |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011030351A2 (en) * | 2009-09-03 | 2011-03-17 | Rubicon Research Private Limited | Taste - masked pharmaceutical compositions |
| WO2013123623A1 (en) * | 2012-02-24 | 2013-08-29 | 量子高科（北京）研究院有限公司 | Oroally disintegrating tablet and preparation method therefor |
| US20150250791A1 (en) * | 2014-03-06 | 2015-09-10 | Bhaskara Rao Jasti | Combining sildenafil with caffeine in an oral disintegrating dosage form |
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