CN112353802A - Vonola fumarate taste masking composition and application thereof - Google Patents
Vonola fumarate taste masking composition and application thereof Download PDFInfo
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Abstract
The invention discloses a Voranolan fumarate taste masking composition and a preparation method thereof, and aims to mask the bitter taste of Voranolan fumarate serving as a medicinal active ingredient and enable the Voranolan fumarate to have good mouthfeel. The drug taste masking composition is prepared by Voranol fumarate and acid type cation exchange resin through a static exchange method, and the weight ratio of the Voranol fumarate to the acid type cation exchange resin is 0.1: 1-3: 1. The Voranolan fumarate taste masking composition prepared by the invention can be further prepared into chewable tablets, dispersible tablets, orally disintegrating tablets, granules and suspensions. Compared with the prior art, the preparation method has the advantages that the bitter taste of the Voranolan fumarate can be effectively covered by adopting an ion exchange technology, the patient compliance is improved, the preparation process is simple, and the preparation method is suitable for industrial production.
Description
Technical Field
The invention relates to the field of pharmaceutical preparations, in particular to a vonola fumarate taste masking composition and application thereof.
Background
Vorexazol fumarate (TAK-438), chemical name 5- (2-fluorophenyl) -1- (3-pyridylsulfonyl) -3-methylaminomethyl-1H-pyrrole fumarate, structural formula shown below:
is a potassium-ion competitive acid blocker (P-CAB) developed by Wuta Kata, Japan (Takeda), first marketed in Japan 12/26.2014. The dosage form on the market is a film-coated tablet. As a reversible proton pump inhibitor, the inhibitor plays a role in stopping gastric acid secretion in advance and inhibiting gastric acid secretion strongly and durably by inhibiting the combination of K + and H + -K + -ATP enzyme (proton pump), has good curative effect on gastric acid-related diseases such as erosive esophagitis, helicobacter pylori infection, duodenal ulcer and gastric ulcer clinically, and also has relatively high tolerance and safety.
Voranolan fumarate itself has a strong bitter taste. Clinical use of tablets has been limited for patients with dysphagia or difficulty, or patients with water intake difficulties, such as the elderly and children.
The common taste masking method comprises adding adjuvants such as correctant, modifying bitter medicinal chemical structure, and coating the medicinal granule or powder with taste masking agent. The bitter taste is reduced by interfering taste buds by adding auxiliary materials, the method is simplest, the cost is low, but the effect is limited, and the effect on extremely bitter and good water-soluble medicines is not good; the structure of the medicament is modified to prepare the prodrug, so that the bad taste is overcome while the curative effect of the bitter medicament is maintained, and the technical difficulty is higher. The taste-masking coating of pharmaceutical granules or powders, due to the technical limitations of the particle size of the coated product, often greater than 200 μm, gives a distinct gritty sensation upon administration and is of poor palatability. At present, no safe and effective Vonola fumarate taste masking scheme exists.
The ion exchange resin can form a compound with ionic drugs, so that the drugs enter the framework of the ion exchange resin to mask the bitter taste of the drugs. The ion exchange resin has chemical inertness and is not absorbed by human body, thus having no local or systemic toxicity and higher safety. And because the dissociation of the drug is based on an ion exchange mechanism, the saliva secreted by the oral cavity is less, the ion concentration is lower, the compound stays in the oral cavity for a short time when the oral drug is orally taken, and the drug enters the stomach before being desorbed in time. Therefore, the bitter taste of the medicine can be effectively covered, and the compliance of patients is improved. When the complex enters the stomach of a human body, the medicine is quickly released in the body under the action of ions.
The drug taste masking composition can be ground into fine powder without destroying the taste masking effect, has no gritty feeling and better palatability, is suitable for dysphagia groups of children, old people and the like, and the final preparation application form of the drug taste masking composition comprises but is not limited to suspension, chewable tablets, orally disintegrating tablets and granules.
Disclosure of Invention
The invention aims to provide a method for preparing a Voranolan fumarate pharmaceutical composition, which masks the bitter taste of a pharmaceutical active ingredient in the Voranolan fumarate pharmaceutical composition, and improves the stability of a medicament and the compliance of a patient.
In order to achieve the purpose, the invention adopts the following technical scheme:
a Vonolanide fumarate taste-masking composition comprises Vonolanide fumarate and an ion exchange resin.
The ion exchange resin is acidic cation exchange resin, and comprises one or more of Amberlite IRP-88, Amberlite IRP-69, Amberlite IRP-64 and Indion 244.
The weight ratio of the vorexant fumarate to the ion exchange resin is 0.1: 1-3: 1.
The particle size D90 of the Vonola fumarate taste masking composition is less than or equal to 100 mu m.
The final preparation application form of the Voranolan fumarate taste-masking composition comprises but is not limited to suspension, chewable tablets, orally disintegrating tablets and granules.
The technical measures adopted for realizing the purpose of the invention are as follows:
a preparation method of Voranolan fumarate taste-masking resin composition prepared by a static adsorption exchange method comprises the following steps:
adding ion exchange resin into Vonopalatine fumarate aqueous solution, continuously stirring until the mixture is in exchange balance, performing suction filtration or centrifugal separation on resin salt and liquid, washing the filtrate with deionized water, drying, crushing, and sieving to obtain Vonopalatine fumarate taste-masking resin composition.
The drying mode is reduced pressure drying, fluidized bed drying or hot air drying.
The crushing mode is mechanical crushing and airflow crushing.
More specifically:
adding ion exchange resin into 0.1-0.5% Vonola fumarate water solution, continuously stirring for 2-10 hr at 20-65 deg.C to exchange balance, suction filtering or centrifuging to separate resin salt and liquid, washing the filtrate with deionized water, drying (drying temperature is 40-70 deg.C), and sieving to obtain Vonola fumarate medicinal composition.
In addition, the invention also discloses a pharmaceutical preparation containing the Vonolatresen fumarate taste masking composition.
The vorexant fumarate taste masking composition provided by the invention can effectively mask taste, and does not influence the quick release of vorexant fumarate.
The invention has the advantages that: compared with the prior art, the Voranolan fumarate and the ion exchange resin are subjected to ion exchange reaction to form the taste masking pharmaceutical composition, so that the bitter taste of Voranolan fumarate is effectively masked, the taste is good, the particle size of the composition is small enough, gritty feeling is avoided, the patient compliance of the drug is improved, especially special dosage forms (such as dry suspension) for certain specific crowds (such as infants and old people with difficulty in swallowing) are ensured to be safer and more effective in taking the drug, the medication pain of patients is reduced, and the taste masking pharmaceutical composition has very important significance for patients who cannot or cannot take common tablets orally. Meanwhile, the preparation process is relatively simple and easy for industrial production.
Drawings
FIG. 1 is a graph showing the dissolution curves of the formulations prepared in examples 6, 7 and 9 of the present invention compared with a commercially available Voranolan fumarate tablet.
Detailed Description
The following examples are presented to further illustrate and explain the present invention. The present disclosure includes, but is not limited to, the following specific examples, which do not specifically limit the scope of the present disclosure.
Example 1 preparation of Voranolan fumarate pharmaceutical composition
The prescription composition is as follows:
| vonola fumarate | 1g |
| Ion exchange resin (Amberlite IRP-88) | 10g |
| Water (W) | 1000mL |
The preparation method comprises the following steps:
mixing Voranolan fumarate and water to obtain medicinal solution, adding ion exchange resin Amberlite IRP-88, stirring at 65 deg.C for 1hr to exchange balance, filtering with Buchner funnel to separate resin salt and liquid, washing with deionized water, drying in hot air circulation oven at 70 deg.C, pulverizing with jet mill, and sieving to obtain Voranolan fumarate medicinal composition. The particle size D90 of the composition was 12 μm.
After dissociation, the Voranolan fumarate content of the Voranolan fumarate pharmaceutical composition is 8.9%.
Example 2 preparation of Voranolan fumarate pharmaceutical composition
The prescription composition is as follows:
| vonola fumarate | 5g |
| Ion exchange resin (Amberlite IRP-69) | 1.67g |
| Water (W) | 1000mL |
The preparation method comprises the following steps:
mixing Vorinopram fumarate and water to obtain medicinal solution, adding ion exchange resin Amberlite IRP-69 at 20 deg.C for 10hr to exchange balance, centrifuging to separate resin salt and liquid, washing the filtrate with deionized water, drying at 50 deg.C in fluidized bed, pulverizing with mechanical pulverizer, and sieving to obtain Vorinopram fumarate medicinal composition. The particle size D90 of the composition was 90 μm.
After dissociation, the Voranolan fumarate content of the Voranolan fumarate pharmaceutical composition is 70.8%.
Example 3 preparation of Voranolan fumarate pharmaceutical composition
The prescription composition is as follows:
| vonola fumarate | 2g |
| Ion exchange resin (Amberlite IRP-64) | 2g |
| Water (W) | 1000mL |
The preparation method comprises the following steps:
mixing Voranolan fumarate and water to obtain medicinal solution, adding ion exchange resin Amberlite IRP-64, stirring at 25 deg.C for 7.5hr to exchange balance, filtering to separate resin salt and liquid, washing the filtrate with deionized water, vacuum drying at 40 deg.C, pulverizing with jet mill, and sieving to obtain Voranolan fumarate medicinal composition. The particle size D90 of the composition was 20 μm.
After dissociation, the Voranolan fumarate content of the Voranolan fumarate pharmaceutical composition is 38.6%.
Example 4 preparation of Voranolan fumarate pharmaceutical compositions
The prescription composition is as follows:
| vonola fumarate | 5g |
| Ion exchange resin (Indion 244) | 10g |
| Water (W) | 1000mL |
The preparation method comprises the following steps:
mixing Vorinopram fumarate and water to obtain medicinal solution, adding ion exchange resin Indion 244 of the prescription amount, continuously stirring at 40 deg.C for 2hr to exchange balance, vacuum filtering to separate resin salt and liquid, washing the filtrate with deionized water, drying at 60 deg.C in fluidized bed, pulverizing with mechanical pulverizer, and sieving to obtain Vorinopram fumarate medicinal composition. The particle diameter D90 of the composition was 50 μm.
After dissociation, the Voranolan fumarate content of the Voranolan fumarate pharmaceutical composition is 26.1%.
Example 5 Vonola fumarate suspension (size: 10 ml: 10mg)
The vorexant fumarate pharmaceutical composition obtained in example 1 was subjected to the following tests.
The prescription composition is as follows:
| raw and auxiliary materials | Weight (mg) |
| Vonoprsyn fumarate pharmaceutical composition | 112 |
| Sorbitol | 1000 |
| Xanthan gum | 15 |
| Glycerol | 500 |
| Sucralose | 4 |
| Nipagin methyl ester | 15 |
| Carmine | 2 |
| Strawberry essence | 5 |
| Make up deionized water to | 10ml |
The preparation process comprises the following steps:
(1) weighing xanthan gum, pregelatinized starch and glycerol according to the prescription amount, adding deionized water accounting for 50% of the prescription amount, and uniformly mixing to obtain a suspension;
(2) weighing sucralose, carmine, ethylparaben and strawberry essence according to the prescription amount, and adding deionized water accounting for 30% of the prescription amount to obtain an aqueous solution;
(3) mixing the suspension with the water solution, adding the Voranolan fumarate composition, stirring to mix well, and adding deionized water to a constant volume to obtain the final product.
Example 6 Vonolasin fumarate chewable tablets (size: 20mg)
The vorexant fumarate pharmaceutical composition obtained in example 2 was subjected to the following tests.
The prescription composition is as follows:
| raw and auxiliary materials | Weight (mg) |
| Vonoprsyn fumarate pharmaceutical composition | 28.5 |
| Direct compression mannitol | 440 |
| Sucralose | 4 |
| Hydroxypropyl cellulose (HPC-SL) | 10 |
| Banana essence | 2.5 |
| |
10 |
| Magnesium stearate | 5 |
The preparation process comprises the following steps:
(1) weighing the taste correcting agent, the adhesive and the disintegrating agent according to the prescription amount, uniformly mixing, adding the voronoi fumarate crude drug composition according to the prescription amount, and uniformly mixing;
(2) weighing the filling agent according to the prescription amount, uniformly mixing the filling agent with the powder in the step (1), adding the essence, the flow aid and the lubricant according to the prescription amount, uniformly mixing, and preparing the powder into tablets by a direct compression method, wherein the tablets have fragrant smell, sweet taste and no gravel feeling.
Example 7 Voranolan fumarate orally disintegrating tablet (size: 10mg)
The vorexant fumarate pharmaceutical composition obtained in example 3 was subjected to the following tests.
The prescription composition is as follows:
| raw and auxiliary materials | Weight (mg) |
| Vonoprsyn fumarate pharmaceutical composition | 25.9 |
| |
60 |
| Lactose | 64.1 |
| |
10 |
| Cross-linked polyvidone | 25 |
| |
10 |
| Cherry essence | 2.5 |
| Magnesium stearate | 2.5 |
The preparation process comprises the following steps:
(1) weighing and uniformly mixing the voronoa fumarate crude drug composition, microcrystalline cellulose, lactose, croscarmellose sodium and aspartame according to the prescription amount;
(2) preparing a soft material by taking deionized water as a wetting agent, granulating by using a 24-mesh sieve, drying at 50 ℃ until the moisture of the granules is less than 4%, and grading by using a 30-mesh sieve;
(3) adding the crospovidone and the magnesium stearate with the prescription amount, mixing uniformly and tabletting.
Referring to the disintegration time limit inspection method of the four general rules 0921 in the pharmacopoeia 2015 year edition: the disintegration time of the orally disintegrating tablets prepared in the above examples was measured, and the degree of disintegration of the orally disintegrating tablets in vivo was measured by volunteers at the same time.
The orally disintegrating tablets of the above examples had an average disintegration time in vitro of 22 seconds.
The orally disintegrating tablet of the above embodiment has an average disintegration time of 25 seconds in the oral cavity, meets the requirements of the orally disintegrating tablet, and has a sweet taste, a fragrant smell, and no gritty feeling.
Example 8 Vonolaside fumarate Dry suspension (Specification: 20mg)
The vorexant fumarate pharmaceutical composition obtained in example 3 was subjected to the following tests.
The prescription composition is as follows:
| raw and auxiliary materials | Weight (mg) |
| Vonoprsyn fumarate pharmaceutical composition | 25.9 |
| Microcrystalline cellulose | 25 |
| |
20 |
| Hydroxypropyl methylcellulose | 11.25 |
| Sucrose powder | 417.35 |
| Orange essence | 0.5 |
The preparation process comprises the following steps:
mixing Voranolan fumarate pharmaceutical composition, sucrose powder, microcrystalline cellulose, xanthan gum and hydroxypropyl methylcellulose uniformly, adding deionized water for granulation, sieving with 30 mesh sieve, air-blast drying at 50 deg.C, grading with 30 mesh sieve, spraying orange essence, and subpackaging 0.5g per bag to obtain dry suspension containing Voranolan fumarate 20 mg.
When in use, 10-50ml of water is added into each package to obtain the suspension with fragrant smell and sweet taste.
According to the settlement volume ratio inspection method of four oral suspensions in Chinese pharmacopoeia 2015 year edition: the sedimentation volume ratio was 0.97.
Example 9 Voronalan fumarate granules (size: 15mg)
The vorexant fumarate pharmaceutical composition obtained in example 4 was subjected to the following tests.
The prescription composition is as follows:
| raw and auxiliary materials | Weight (mg) |
| Vonoprsyn fumarate pharmaceutical composition | 57.4 |
| Sucrose powder | 413.35 |
| Arabic gum | 15 |
| Hydroxypropyl methylcellulose | 13.75 |
| Orange essence | 0.5 |
The preparation process comprises the following steps:
mixing Voranolan fumarate pharmaceutical composition, sucrose powder and acacia, adding 2% hypromellose water solution to make into soft mass, sieving with 20 mesh sieve, performing granulation by swinging, blowing at 50 deg.C, grading with 20 mesh sieve, spraying orange essence, and packaging to obtain granule containing Voranolan fumarate 15mg per bag at a weight of 0.5 g.
When in use, each bag is taken with 10-50ml of water, and the tea is fragrant and sweet.
Experimental example 1, taste masking composition preparation was dissolved.
Dissolution comparison tests were carried out on the self-formulations (formulations prepared in examples 6, 7 and 9 of the present invention) and the reference formulation (commercial voronol fumarate) according to the second method of the dissolution and release measurements of 0931, the fourth general rule of pharmacopoeia 2015, year round. The measurement conditions are as follows.
Rotating speed: 50rpm
Volume of dissolution medium: 900mL
Dissolution medium: hydrochloric acid solution of pH1.2
Sampling time points are as follows: 5min, 10min, 15min, 20min, 30min
The determination method comprises the following steps: high performance liquid chromatography with detection wavelength of 230nm
Whether the two dissolution curves are similar or not is evaluated by a similarity factor method (f2) in a model-independent method according to the determination of the dissolution curve of the common oral solid preparation and a comparison guide principle. Comparing the dissolution rate of the self-prepared product with that of a reference preparation, and when the calculated f2 value is between 50 and 100, the two dissolution curves are considered to have no significant difference, and the closer the f2 value is to 100, the higher the similarity is; otherwise, they are not similar, i.e. there is a significant difference. Particularly, when the 15min dissolution rate of the reference preparation is more than or equal to 85 percent and the 15min dissolution rate of the self-prepared product is also more than or equal to 85 percent, the f2 is not needed to be compared, and the self-prepared product is directly judged to be similar to the reference preparation in dissolution rate.
The f2 calculation formula is as follows:
the results of the dissolution profile measurements are shown in Table 1 and FIG. 1.
As shown in the table above, the dissolution rates of the preparations in examples 6, 7, 9 and the reference preparation are all over 85% at 15min, which shows that the preparation prepared from the vorexant fumarate pharmaceutical composition of the invention has the dissolution rate similar to that of the commercially available vorexant fumarate tablet.
Experimental example 2: mouth taste experiment
The final formulations of the vorexant fumarate compositions prepared in example 5, example 8 and example 9 were added to water to make a tasting sample containing 1mg vorexant fumarate per ml, with 1mg/ml vorexant fumarate solution as a bitter base. 12 healthy volunteers (6 men and 6 women) aged 22-28 years were selected, rinsed 3 times with water before mouth-tasting, 1ml of mouth-tasting sample was dropped in the center of the tongue and left in the mouth for about 30s, and the degree of gritty sensation and bitterness were recorded, followed by mouth-rinsing. The bitterness was from 0 to 4, 0 no bitterness, 1 slightly bitter, 2 acceptable bitterness, 3 moderately bitter, and 4 strongly bitter. The results are shown in Table 2.
Claims (9)
1. Voranolan fumarate taste-masking composition, which is characterized by comprising Voranolan fumarate and ion exchange resin.
2. Vonolanide fumarate taste masking composition of claim 1, wherein the ion exchange resin is an acidic cation exchange resin comprising one or more of Amberlite IRP-88, Amberlite IRP-69, Amberlite IRP-64, index 244.
3. Voranolan fumarate taste-masking composition according to claim 1, wherein the weight ratio of Voranolan fumarate to ion-exchange resin is from 0.1: 1 to 3: 1.
4. Voranolan fumarate taste-masking composition according to claim 1, wherein the particle size D90 is ≤ 100 μm.
5. The process for the preparation of a vorexant fumarate taste-masking composition of claim 1, wherein the vorexant fumarate taste-masking resin composition is prepared by static adsorption-exchange.
6. A process for the preparation of a Vonola fumarate taste masking composition according to claim 5, characterized in that: adding ion exchange resin into Vonopalatine fumarate aqueous solution, continuously stirring until the exchange balance is reached, carrying out suction filtration or centrifugal separation on resin salt and liquid, washing the filtrate with deionized water, drying, crushing and sieving to obtain the Vonopalatine fumarate taste-masking resin composition.
7. The process for preparing a vorexant fumarate taste-masking resin composition of claim 6, characterized in that: the drying mode is reduced pressure drying, fluidized bed drying or hot air drying.
8. The process for preparing a vorexant fumarate taste-masking resin composition of claim 6, characterized in that: the crushing mode is mechanical crushing and airflow crushing.
9. Voelargol fumarate taste masking composition according to claim 1, characterized in that: the final preparation application form of the Voranolan fumarate taste-masking composition comprises but is not limited to suspension, chewable tablets, orally disintegrating tablets and granules.
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Cited By (2)
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| CN115721611A (en) * | 2022-12-09 | 2023-03-03 | 北京斯利安药业有限公司 | Vonola fumarate dry suspension and preparation method thereof |
| WO2024027794A1 (en) | 2022-08-05 | 2024-02-08 | 哈尔滨市康隆药业有限责任公司 | Taste-masking microsphere, preparation process therefor, and use thereof |
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| WO2024027794A1 (en) | 2022-08-05 | 2024-02-08 | 哈尔滨市康隆药业有限责任公司 | Taste-masking microsphere, preparation process therefor, and use thereof |
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