CN112587476B - Novel sildenafil gel formulation suitable for neonatal arterial hypertension and preparation method thereof - Google Patents
Novel sildenafil gel formulation suitable for neonatal arterial hypertension and preparation method thereof Download PDFInfo
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
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- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/42—Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
- A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
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- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
Abstract
A sildenafil gel new formulation suitable for neonatal arterial hypertension is composed of bulk drug, solubilizing fast solvent, gel matrix, essence and water; the bulk drug is sildenafil citrate, the solubilizing quick-dissolving agent is an oral surfactant, and the gel matrix is a gelatin-sucrose matrix; in the new gel form, the addition amount of the solubilization cosolvent is 2-7%, the addition amount of the gel matrix is 10-15%, and the addition amount of the bulk drug is 1 mg/mL-bulk drug saturation when the new gel form is in a solution state. The sildenafil semisolid gel preparation can wrap a medicine, cover up bitter taste, improve the swallowing effect of the medicine, not inhibit the curative effect of the medicine and improve the compliance of a patient.
Description
Technical Field
The invention relates to a novel children drug dosage form, in particular to a novel sildenafil gel dosage form suitable for neonatal arterial hypertension and a preparation method thereof, and belongs to the technical field of children special drugs and preparation thereof.
Background
Persistent pulmonary hypertension of the newborn (PPHN) is a common critical condition in the neonatal period and the mortality of the infant is high. At present, the main treatment principle of expanding pulmonary artery blood vessels and reducing pulmonary resistance is clinically used. The traditional treatment method of PPHN is to adopt high-frequency concussion ventilation technologyCombined with cardiotonic therapy (dobutamine, dopamine) to improve systemic hemodynamics, enhance cardiac output and systemic O 2 Transport, but over-ventilation increases the chance of periventricular leukomalacia and the occurrence of hearing abnormalities; in addition, PPHN may also be treated with vasodilator drugs such as magnesium sulfate, prostacyclin, lung surfactant, etc., but these drugs do not selectively dilate the pulmonary artery and have limited clinical efficacy; at present, new therapies such as Inhalation of Nitric Oxide (iNO), extracorporeal membrane oxygenation (ECMO) and the like are also used for treating PPHN, and the mortality rate is obviously reduced.
Sildenafil Citrate (SC) is a selective inhibitor of phosphodiesterase type 5 (PDE-5). PDE-5 is an enzyme for metabolizing cyclic guanosine monophosphate (cGMP), which can convert cGMP into guanylate, and SC can inhibit the enzymatic activity of PDE-5 to reduce cGMP degradation into GMP, promote intracellular cGMP accumulation, accelerate the opening frequency of potassium channel by activating phosphokinase and protein phosphorylation, hyperpolarize cell membrane, inhibit calcium influx into cells, enhance transduction of NO-cGMP signal pathway, promote cGMP-mediated relaxation of vascular smooth muscle (including pulmonary vascular smooth muscle), dilate blood vessels, improve blood flow dynamics, and increase intracellular cGMP level can promote relaxation of vascular smooth muscle in lungs. In recent years, sildenafil is clinically used for treating pulmonary hypertension, can activate a NO-cGMP passage to expand pulmonary artery blood vessels, has similar effect to NO inhalation treatment, is convenient for SC administration and relatively low in price, is beneficial to improving the compliance of patients, and has relatively wide prospect in the aspect of treating PPHN.
SC is a white or off-white crystal with the chemical name 1- [ 4-ethoxy-3- [5- (6, 7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo [4, 3 d)]Pyrimidine)]Benzene sulfonyl group]-4-methylpiperazine citrate having the chemical structural formula C 28 H 38 N 6 0 11 S, relative molecular weight is 666.7 Da. The sildenafil citrate is marketed in dosage forms such as tablets, suspensions and the like, mainly adopts an oral administration mode, and has low bioavailability due to the low solubility (slightly soluble) of SC in water, so that the action effect of the drug is limited to a certain extent. Clinically, sildenafil citrate is mainly administered in the form of oral tablets, oral suspensions and the like, but no sildenafil preparation special for newborns exists at present. Clinically, the sildenafil citrate tablet is mainly ground into powder, simply weighed, dispersed in drinking water and then taken by a newborn. The method has the disadvantages of complicated operation, inaccurate administration dosage and reduced curative effect; dysphagia of newborn babies, and throat choking easily occurs; poor stability and the like.
Disclosure of Invention
Aiming at the defects of the prior art, the invention provides the sildenafil semisolid gel preparation suitable for children patients with persistent pulmonary hypertension, which can wrap the medicine, cover up the bitter taste, improve the swallowing effect of the medicine, not inhibit the curative effect of the medicine and improve the compliance of patients.
The technical scheme adopted by the invention for solving the technical problems is as follows:
a sildenafil gel new formulation suitable for neonatal arterial hypertension is composed of bulk drug, solubilizing fast solvent, gel matrix, essence and water;
the bulk drug is sildenafil citrate, the solubilizing quick-dissolving agent is an oral surfactant, and the gel matrix is a gelatin-sucrose matrix;
in the new gel form, the addition amount of the solubilization cosolvent is 2-7%, the addition amount of the gel matrix is 10-15%, and the addition amount of the bulk drug is 1 mg/mL-bulk drug saturation when the new gel form is in a solution state.
Further, in the gel matrix, the mass ratio of gelatin to sucrose is 10:3, the total adding amount of the jelly matrix in the new jelly dosage form is 10-15%.
Further, the oral surfactant is poloxamer F127.
Furthermore, the addition amount of the poloxamer F127 in the new jelly dosage form is 5 percent.
Preferably, the sildenafil gel new formulation suitable for neonatal arterial hypertension consists of bulk drug, a solubilizing quick solvent, a gel matrix, essence and water;
the bulk drug is sildenafil citrate, the solubilizing quick-dissolving agent is poloxamer F127 serving as an oral surfactant, and the gel matrix is a gelatin-sucrose matrix;
in the new gel form, the addition amount of the solubilization cosolvent is 5%, the addition amount of the gel matrix is 13%, and the addition amount of the bulk drug is 1 mg/mL-bulk drug saturation when the new gel form is in a solution state.
The preparation method of the novel sildenafil gel formulation suitable for neonatal arterial hypertension comprises the following steps: weighing oral surfactant with corresponding mass, stirring at room temperature, dissolving in distilled water, adding sildenafil citrate as raw material into the clear solution, stirring at room temperature, adding gelatin-sucrose matrix and essence with corresponding mass, heating in 70 deg.C water bath, stirring, cooling to 37 deg.C, and cooling to solidification state at low temperature.
Compared with the prior art, the invention has the beneficial effects that:
the novel jelly preparation is a jelly semi-solid preparation, has certain viscoelasticity, is easy to chew, can be slowly degraded after contacting with the oral cavity, has no stimulation, inflammation or bitter taste, can be eaten under the condition of no drinking water, and can reduce or avoid the risks of pneumonia or suffocation and the like caused by the fact that a patient with swallowing difficulty sucks food into the trachea compared with a low-viscosity liquid; in addition, the gel preparation can wrap the medicine and cover the smell of the medicine; the swallow of the patient is facilitated, and the foreign body sensation during the swallow is reduced; the gel preparation has certain water binding capacity, so that the drug can be prevented from remaining in the oral cavity, the curative effect of the drug is reduced, and the compliance of a patient is improved; based on the characteristics, the gel preparation is suitable for newborn patients with weak bodies or dysphagia, and is helpful for enhancing the treatment effect of the medicine;
according to the invention, sildenafil citrate is used as a raw material medicine, and a solubilizing quick-dissolving agent which can achieve a solubilizing quick-dissolving effect on sildenafil citrate and a gel matrix which can achieve a good gelling effect are used as auxiliary materials to prepare a sildenafil citrate gel preparation; the theoretical drug loading rate is 0.8-2.5 mg/g, the drug dissolution rate can meet the treatment requirement, the gel preparation is a semisolid gel-state neonatal special sildenafil preparation, has great advantages in the aspects of stability, dosage accuracy, convenience in use, patient compliance and the like, facilitates the neonate to swallow, ensures the accurate administration dosage and achieves the purpose of treating the pulmonary hypertension of the neonate.
Drawings
FIG. 1 shows gel water holding capacity of gelatin matrices of different concentrations;
FIG. 2 shows the storage modulus G' and loss modulus G "(a) and loss factor tan δ (b) for gels of varying gelatin matrix concentrations;
FIG. 3 is the water binding capacity of gels at different sucrose concentrations;
FIG. 4 shows the storage modulus G' and loss modulus G "(a) and loss factor tan δ (b) for gels of varying sucrose base concentrations.
Detailed Description
The invention will be further explained and illustrated with reference to preferred embodiments.
Example 1: the sildenafil gel new formulation suitable for neonatal arterial hypertension consists of bulk drug, a solubilizing fast solvent, a gel matrix, essence and water;
the bulk drug is sildenafil citrate, the solubilizing quick-dissolving agent is oral surfactant poloxamer F127, and the gel matrix is a gelatin-sucrose matrix;
in the new gel form, the addition amount of the solubilization cosolvent is 5%, the addition amount of the gel matrix is 13%, and the addition amount of the bulk drug is 2mg/mL when the new gel form is in a solution state.
The preparation method of the novel sildenafil gel formulation suitable for neonatal arterial hypertension comprises the following steps: weighing oral surfactant with corresponding mass, stirring at room temperature, dissolving in distilled water, adding sildenafil citrate raw material medicine with required mass into the clear solution, stirring at room temperature, adding gelatin-sucrose matrix and essence with corresponding mass, heating in water bath at 70 deg.C, stirring, cooling the hot solution to 37 deg.C under stirring in water bath, and cooling at low temperature to solidification state.
Example 2: solubilization of sildenafil citrate with different concentrations of different oral surfactants: poloxamer and polyethylene glycol which are commonly used in the field are taken as selected objects, 1%, 2%, 5% and 7% of poloxamer F127 solution, poloxamer F68 solution and polyethylene glycol 4000 solution are respectively prepared to be used as to-be-tested solutions, the to-be-tested solutions are stirred and dissolved at room temperature, and excessive sildenafil citrate raw material medicines are respectively added into the to-be-tested solutions with different concentrations to prepare sildenafil citrate supersaturated solutions. Placing the supersaturated solution in a water bath constant temperature oscillator, shaking at 25 deg.C and 100rpm, sampling after 48h, centrifuging at 10000r/min for 10min to obtain supernatant, diluting the supernatant sample with mobile phase to a certain multiple, measuring absorbance with sildenafil citrate reference solution (std) as reference, and calculating the saturation concentration of the medicine by external standard point method. Each concentration was made in parallel with 3 parts. Wherein std is prepared: the sildenafil citrate reference solution is prepared by accurately weighing 35mg of sildenafil citrate raw material medicine in a 50mL volumetric flask, taking 7mL of triethylamine as a solvent, diluting the triethylamine with Waaha water to 1000mL, adjusting the pH value to 3.0 with phosphoric acid, diluting to a constant volume to obtain a sample 1, accurately weighing 2mL of the sample 1 in the 50mL volumetric flask, diluting the sample to a constant volume to a scale line with the mobile phase (pH 3.0 triethylamine-methanol-acetonitrile (58: 25: 17, v/v/v) as a mobile phase, and preparing the sildenafil citrate reference solution with the pH value of 3.0). And (3) carrying out ultraviolet full-wavelength scanning on the solution within the wavelength range of 250-450 nm by using an ultraviolet spectrophotometer, measuring the ultraviolet spectrum of the solution, and determining the maximum absorption wavelength so as to determine the optimal detection wavelength of sildenafil citrate HPLC. The final measurement results are shown in the following table.
Sildenafil citrate is known to have a water solubility of 3.5 mg/mL. As can be seen from the above table, in each of the 1% and 2% poloxamer surfactants, sildenafil citrate has a solubility that is slightly lower than its solubility in water, and has no solubilizing effect; in 5% concentration of poloxamer F68, sildenafil citrate has no significant increase in solubility compared to its solubility in water, and increasing the concentration (7%) has limited solubilizing effect; in 5% of poloxamer F68, the solubility of sildenafil citrate is increased to a certain extent compared with the solubility in water, the dissolution speed of the sildenafil citrate in 5% of poloxamer F127 is obviously increased compared with the dissolution speed of the sildenafil citrate in water, and the increasing concentration (7%) has limited solubilizing effect; in 1% concentration of polyethylene glycol 4000, the solubility of sildenafil citrate is greatly increased compared with the solubility of sildenafil citrate in water, but in the stirring and dissolving process, the polyethylene glycol 4000 solution is easy to foam, the defoaming time is long, the preparation of sildenafil citrate gel preparation is not facilitated, and polyethylene glycol 4000 solutions in other concentration ranges have no solubilizing effect on sildenafil citrate.
Example 3: the physical appearance of the jelly was evaluated by adjusting the concentration of the gelatin matrix to 10%, 12%, 14%, 16% (w/v) and the concentration of the gelatin matrix to 0.5%, 1%, 2% (w/v) of the carrageenan matrix, respectively, based on example 1, and the transparency, roughness, strength, odor, etc. were evaluated.
Sensory characteristic test analysis shows that products with the gelatin matrix concentration from 10% to 16% all present a yellow transparent semi-solid state without special smell, the texture of the products with the gelatin matrix at each concentration is continuous and uniform, the surface is smooth, and the products have certain elasticity, the color of the products is deepened with the increase of the gelatin concentration, the elasticity is reduced, the strength is increased, and the swallowing and chewing load of patients is increased.
The products obtained by the carrageenan matrixes with different concentrations are in a light yellow transparent semi-solid state, the texture is continuous and uniform, the surface is smooth, certain special smell is generated, the viscosity of the carrageenan matrix with low concentration of 0.5% is higher, the elasticity is poorer, the strength of the carrageenan matrix is increased along with the increase of the concentration, the administration of patients with dysphagia is not facilitated, in addition, the gelation state of the carrageenan solution has multiple properties, the gelation temperature is greatly influenced by the room temperature, and the requirements on the operation conditions are strict.
Example 4: the water retention and viscoelasticity of the gel obtained were measured while adjusting the concentrations of the gelatin base to 10%, 12%, 14%, 16% and 18% (w/v) in addition to example 1.
Determination of Water holding Property: taking 1mL of solution which is not coagulated, putting the solution into a 1.5mL printing tube, weighing the solution after the solution is gelled, putting the solution into a freezing high-speed centrifuge, centrifuging the solution at the rotating speed of 10000r/min for 20min, absorbing upper water, weighing the solution again, calculating the water holding capacity of the solution according to the formula shown below, and preparing 3 parts of each sample in parallel.
In the formula: m 1 The mass per gram of a centrifugal tube filled with jelly before centrifugation;
M 2 the tubes were centrifuged in mass/g after moisture had been removed.
Measurement criteria for viscoelasticity: the gel is prepared into a circular sheet with the diameter of 50mm and the thickness of 5mm, a cone plate clamp with the model number of 104717, the cone angle of 4: 0: 43 (deg: min: sec), the cone diameter of 40mm and the truncation parameter of 109 mu m is selected, an AR-G2 rotary rheometer is used for carrying out dynamic frequency test in a flow mode, the scanning frequency is 0.1-100 rad/s, the instrument balance time is 5s, the sample test average time is 30s, all tests are carried out under the condition of normal temperature (25 ℃), loss factors are calculated according to the formula shown below, and 3 parts of each sample is prepared in parallel.
tanδ＝G″/G′
In the formula: tan delta is the loss factor;
g' is loss modulus/Pa;
g' is storage modulus/Pa.
The test results are shown in fig. 1 and fig. 2(a) and (b). As can be seen from figure 1, the gelatin concentration is 10%, the water binding capacity of the sample is obviously reduced and becomes stable along with the increase of the gelatin concentration, the water binding capacity of the gel preparation plays an important role in improving the compliance of patients, and when the water binding capacity is high, the gel can be prevented from being adhered to oral mucosa, the foreign body sensation of the patients during taking is reduced, and the swallowing of newborns is more convenient.
As can be seen from FIG. 2, dynamic frequency scanning is performed on gel agents with gelatin matrixes of different concentrations in the range of 0.1-100 rad/s in the flow mode to obtain the loss modulus (G ') and the storage modulus (G') of the gel agent. G' represents the loss of energy in the material under the action of strain and reflects the viscosity of the material; g ' represents the storage condition of energy and reflects the elasticity of the material, the ratio of G ' to G ' is a loss factor (tan delta), the size of the loss factor can evaluate the viscoelasticity of the material, and the larger tan delta is, the stronger the viscosity of the material is, and the better the fluidity is; otherwise, the higher the elasticity is, the more obvious the solid properties are.
As can be seen from FIG. 1, in the range of 0.1 to 100rad/s, G' of the measured samples are all an order of magnitude greater than G ", tan delta is less than 1, and as the angular frequency ω increases, tan delta of the measured samples increases slightly, indicating that the elasticity of the measured samples is higher than that of the viscosity, and the elasticity of the samples can be reduced by shearing. Of the 5 concentrations, the 10% gelatin matrix sample had a lower tan δ, indicating that this concentration of gelatin matrix is less viscous and more elastic; and can gradually change from solid state to liquid state in the chewing process to increase the fluidity. This is advantageous in reducing the use load of the patient when taking the medicine by compression; is easier to be taken by patients with dysphagia.
Example 5: based on example 1, the concentrations of sucrose in the gelatin-sucrose base were adjusted to 1%, 2%, 3%, 4%, and 5% (w/v), respectively, and the water-holding capacity and viscoelasticity of the gel obtained were measured.
As can be seen from FIG. 3, the water binding capacity of the jelly agent fluctuates only slightly when the sucrose concentration is increased from 1% to 5%. This indicates that the change in sucrose concentration has less effect on the water binding capacity of the sample at sucrose concentrations of 1% to 5%, and it can be seen from the figure that at sucrose concentration of 3%, the water binding capacity of the sample is relatively higher, more favorable for chewing swallowing, relatively less load for swallowing, and more convenient for the neonate to swallow.
"10 + 1" in FIG. 4 indicates a gelatin concentration of 10% (w/v), a sucrose concentration of 1% (w/v) in the matrix, and so on. As shown in FIG. 4, in the range of 0.1 to 100rad/s, G of the tested sample is larger than G' by an order of magnitude, tan delta is smaller than 1, tan delta of the tested sample is slightly increased along with the increase of angular frequency omega, elasticity of the tested sample is higher than viscosity, and the elasticity of the sample can be reduced by shearing. The matrix sample of 10% gelatin-3% sucrose has lower tan delta, which shows that the viscoelasticity of the matrix sample of gelatin-sucrose with the concentration is lower, the fluidity of the matrix can be increased through chewing, the chewing of patients with dysphagia is facilitated, and the compliance of patients and the medication compliance of patients with low swallowing function can be improved.
Example 6: selecting the content of sildenafil citrate raw material medicines: weighing a surfactant with corresponding mass, stirring and dissolving the surfactant in a certain amount of distilled water at room temperature, then respectively adding sildenafil citrate raw material medicine with corresponding mass into a clarified solution, stirring and dissolving the mixture at room temperature to prepare sildenafil citrate solution with 1mg/mL, 2mg/mL and 3mg/mL, then adding gelatin, sucrose and a proper amount of essence with corresponding mass, wherein the contents of the gelatin, the sucrose and the surfactant are the same as those in example 1, heating and stirring the mixture in a water bath at 70 ℃ for dissolving, then gradually cooling the hot solution to 37 ℃ under the stirring of the water bath, and then placing the hot solution at a low temperature for cooling to a solidification state.
Determining the content of the sildenafil citrate gel preparation in a solution state: sildenafil citrate control solution (same as example 2) is prepared and filtered by a 0.45 μm organic filter membrane, 20 μ L of subsequent filtrate is injected into a high performance liquid chromatograph (chromatographic conditions: ZORBAX SB-C18 chromatographic column (4.6X 250mm, 5-Micron; sample introduction amount: 20 μ L; flow rate: 1.0 mL/min; column temperature: 30 ℃; detection wavelength: 290 nm). Sample preparation: 1mL of sildenafil citrate gel preparation solution of 1mg/mL, 2mg/mL and 3mg/mL is taken out of a 50mL volumetric flask, the mass of the taken solution is precisely weighed, the gel solution is diluted by a mobile phase (same as the example 2) and the volume is fixed to a scale, and a sample solution is obtained. Injecting samples by the same method, recording peak areas, respectively calculating the drug content in the gel solution according to an external standard one-point method, and preparing 3 parts of each sample in parallel. The results of the drug content (Mean ± SD, n ═ 3) of sildenafil citrate gel preparation in solution state are shown in the following table:
the effective drug content in the gel solution is measured, the volume concentration of the drug is converted into the mass concentration, the further evaluation of the curative effect of the preparation is facilitated, and the drug content is continuously increased along with the increase of the drug concentration as can be seen from the table. Wherein, the drug content of the solution with the concentration of 1mg/mL is 0.737 +/-0.211 mg/g; the drug content of the solution with the concentration of 2mg/mL is 1.654 +/-0.009 mg/g; the drug content of the solution with the concentration of 3mg/mL is 2.435 +/-0.013 mg/g, and within the range of 1 mg/mL-3 mg/mL, the concentration of the drug dosage has a certain linear relation with the drug content, and the drug content can be used as the reference for setting the drug content of the gel preparation.
Determination of drug content of sildenafil citrate gel preparation in semisolid state: preparing sildenafil citrate reference solution, filtering with 0.45 μm organic filter membrane, and injecting 20 μ L of the filtrate into high performance liquid chromatograph. Sample preparation: precisely weighing 1g of semisolid gel from 1mg/mL, 2mg/mL and 3mg/mL semisolid citric acid sildenafil gel preparations respectively, cutting the semisolid gel into small blocks with uniform size, putting the small blocks into a 50mL volumetric flask, adding a proper amount of mobile phase, performing ultrasonic treatment under the condition of 50Hz until the gel is completely dissolved, and adding the mobile phase to a constant volume after cooling to room temperature. Injecting sample by the same method, recording peak area, respectively calculating the drug content in the semisolid gel according to an external standard one-point method, and preparing 3 parts of each sample in parallel. The results of the drug content (Mean ± SD, n ═ 3) of sildenafil citrate gel preparation in the semisolid state are shown in the following table:
the determination of the drug content of the preparation is an important method for judging the quality of the preparation, controlling and evaluating the quality of the preparation. As can be seen from tables 3-9, the drug content of the jelly formulation is increasing with the increase of the drug concentration. Wherein, the drug content of the semisolid gel with the concentration of 1mg/mL is 0.860 +/-0.021 mg/g; the drug content of the semisolid gel with the concentration of 2mg/mL is 1.731 +/-0.016 mg/g; the drug content of the semisolid gel with the concentration of 3mg/mL is 2.506 +/-0.012 mg/g, and in the range of 1 mg/mL-3 mg/mL, the concentration of the drug dosage has a certain linear relation with the drug content, and the drug content can be used as the reference for setting the drug content of the gel preparation.
The drug dissolution rate of sildenafil citrate gel preparation is determined as follows: sample preparation: precisely weighing 10g of jelly from 1mg/mL, 2mg/mL and 3mg/mL semisolid sildenafil citrate jelly preparations respectively, and cutting the jelly into small blocks with uniform size. According to a second method (paddle method) for determining the dissolution rate in Chinese pharmacopoeia (2015 edition), 900mL of hydrochloric acid solution with pH of 1.0 and 900mL of distilled water are taken as dissolution media respectively, the rotation speed is 50rpm/min, a stirring paddle and a dissolution instrument are well adjusted, the prepared sample is put into a dissolution cup, the stirring paddle is added into the dissolution media (37 +/-0.5 ℃), timing is started, then sampling is carried out at intervals of 5, 10, 15, 30, 45, 60 and 120min, 5mL of dissolution media is sampled each time (and simultaneously 5mL of dissolution media is supplemented), sample liquid is filtered by a 0.45 mu m water-based filter membrane and injected into a test tube, 20 mu L of subsequent filtrate is injected into a high performance liquid chromatograph for determination, the peak area is recorded, the accumulation of the semisolid sildenafil dissolution rate gel preparation is calculated according to the formula shown below, and 3 parts of each sample are prepared in parallel.
In the formula: a. the To pair The peak area of sildenafil citrate control solution is shown;
A 0 the peak area of the solution at the time 0 of the sildenafil citrate gel preparation (the peak area at the time is 0);
A n the peak area of the solution at the nth time point of the sildenafil citrate gel preparation (n is more than or equal to 1);
C for is to Is the concentration (mg/mL) of sildenafil citrate control solution;
V 1 to supplement dissolution media volume/mL (5 mL in this experiment);
V 2 volume of dissolution medium/mL (900 mL in this experiment);
m theory of the invention Is the theoretical drug content/mg of sildenafil citrate gel preparation.
The drug dissolution (Mean ± SD, n ═ 3) results of sildenafil citrate gel formulations in hydrochloric acid medium at pH 1.0 are shown in the following table:
the results of the drug dissolution (Mean + -SD, n is 3) of sildenafil citrate gel preparation in distilled water medium are shown in the following table:
from the above results, it can be seen that the sildenafil citrate gel formulations at three concentrations in hydrochloric acid medium with pH 1.0 already reach more than 90% at 5min (0.083 h). Wherein the dissolution rate of the sildenafil citrate gel preparation with the concentration of 3mg/mL is 94.0% +/-2.80%; the dissolution rate of the sildenafil citrate gel preparation of 2mg/mL is 92.8% +/-0.95%; the dissolution rate of 1mg/mL sildenafil citrate gel preparation is 96.1% +/-1.83%. Within the next 2h, the dissolution rates of sildenafil citrate gel preparations with three concentrations slightly fluctuate but are all kept at about 95%, the medicine is basically and completely dissolved, and the dissolution behavior is better.
In a distilled water medium, the sildenafil citrate gel preparation with three concentrations has the release degree of more than 85 percent at 5min (0.083 h). Wherein, the dissolution rate of the sildenafil citrate gel preparation with the concentration of 3mg/mL is 88.2% +/-1.15%; the dissolution rate of the sildenafil citrate gel preparation of 2mg/mL is 90.2% +/-1.26%; the dissolution rate of 1mg/mL sildenafil citrate gel preparation is 88.6% +/-4.98%. Within the next 2h, the dissolution rates of sildenafil citrate gel preparations with three concentrations slightly fluctuate, but are all kept at about 90%. However, sildenafil citrate gel formulations have a lower dissolution rate in distilled aqueous media than in hydrochloric acid at pH 1.0. Therefore, hydrochloric acid having a pH of 1.0 is considered to be an optimum dissolution medium for sildenafil citrate.
In conclusion, hydrochloric acid with the pH value of 1.0 can be considered as the optimal dissolution medium of sildenafil citrate, the sildenafil citrate gel preparation has better dissolution rate in the dissolution medium, the drug dissolution rate is over 90 percent within 5min, and the drug dissolution rate is maintained at about 95 percent within 2h, so that the drug can be fully released, and the absorption of a patient is facilitated.
The above description is only an exemplary embodiment of the present invention, and is not intended to limit the scope of the present invention. In order that the components of the present invention may be combined without conflict, it is intended that all equivalent changes and modifications made by those skilled in the art without departing from the spirit and principles of the present invention shall fall within the protection scope of the present invention.
Claims (2)
1. A sildenafil gel formulation suitable for neonatal arterial hypertension is composed of raw material medicines, a solubilizing quick-dissolving agent, a gel matrix, essence and water:
the bulk drug is sildenafil citrate, the solubilizing quick-dissolving agent is poloxamer F127 serving as an oral surfactant, and the gel matrix is a gelatin-sucrose matrix:
in the gel formulation, the addition amount of the solubilization cosolvent is 5% w/v, the addition amount of the gel matrix is 13% w/v, and the addition amount of the bulk drug is 1 mg/mL-bulk drug saturation when the gel formulation is in a solution state; wherein the mass ratio of gelatin to sucrose in the gel matrix is 10: 3.
2. A method of preparing sildenafil gel formulation suitable for neonatal arterial hypertension according to claim 1, comprising the steps of: weighing oral surfactant with corresponding mass, stirring at room temperature, dissolving in distilled water, adding sildenafil citrate as raw material into the clear solution, stirring at room temperature, adding gelatin-sucrose matrix and essence with corresponding mass, heating in 70 deg.C water bath, stirring, cooling to 37 deg.C, and cooling to solidification state at low temperature.
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| WO2014119985A2 (en) * | 2013-01-31 | 2014-08-07 | Garcia Pérez Miguel Ángel | Pharmaceutical composition comprising a selective phosphodiesterase enzyme inhibitor in oral gel form |
| CN104274391A (en) * | 2014-10-08 | 2015-01-14 | 哈尔滨坤盟医药科技有限公司 | Rifaximin-containing pharmaceutical preparation |
| CN104922057A (en) * | 2015-05-31 | 2015-09-23 | 黑龙江佰彤儿童药物研究有限公司 | Child-type oral anti-epileptic pharmaceutical gel unit and preparation method thereof |
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| WO2014119985A2 (en) * | 2013-01-31 | 2014-08-07 | Garcia Pérez Miguel Ángel | Pharmaceutical composition comprising a selective phosphodiesterase enzyme inhibitor in oral gel form |
| CN104274391A (en) * | 2014-10-08 | 2015-01-14 | 哈尔滨坤盟医药科技有限公司 | Rifaximin-containing pharmaceutical preparation |
| CN104922057A (en) * | 2015-05-31 | 2015-09-23 | 黑龙江佰彤儿童药物研究有限公司 | Child-type oral anti-epileptic pharmaceutical gel unit and preparation method thereof |
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| 明胶的凝胶特性及多糖对明胶凝胶特性的影响;陈海华;《粮油加工》;20090531(第5期);第130页1．3．1 明胶凝胶的制备，第131页1.3.4蔗糖、氯化钙、氯化钠对明胶凝胶强度的影响，第131页右栏最后一段-第132页左栏第一段 * |
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