KR20110012608A - Granisetron orally disintegrating tablets and manufacturing processes thereof - Google Patents

Abstract

PURPOSE: An orally disintegrating tablet(ODT) containing granisetron or pharmaceutically acceptable salt thereof is provided to shield the bitter taste of granisetron and to improve administration compliance. CONSTITUTION: An orally disintegrating tablet contains granisetron or pharmaceutically acceptable salt thereof, sweetener and flavoring, spray-dried lactose hydrate, D-mannitol or mixture thereof as an excipient, crospovidone as a disintegrant, a colloidal silicon dioxide as a first lubricant, and sodium stearylfumarate as a second lubricant. A method for manufacturing the orally disintegrating tablet comprises: a step of pulverizing granisetron or pharmaceutically acceptable salt thereof in a 50um of particle size; a step of adding sweetener and flavoring and mixing; a step of adding excipient and first lubricant for first lubrication; a step of adding crospovidone and second lubricant; and a step of tabletizing.

Description

Granisetron Orally Disintegrating Tablets and Manufacturing Processes

The present invention relates to an orally disintegrating tablet (GDT) of Granisetron and a method for preparing the same. More specifically, in-vitro disintegration time is 30 seconds or less and oral In addition to the rapid disintegration in the interior, Granisetron's oral cavity enhances compliance, so that patients with swallowing disorders, especially those undergoing long-term chemotherapy, can be taken without water by masking the unique bitter taste of Granisetron. It relates to a fast disintegrating tablet and a method of manufacturing the same.

Recently, in the pharmaceutical industry, a technique for preparing oral disintegrating tablets has been spotlighted. Intraoral disintegrating tablets disintegrate and dissolve rapidly by saliva in the oral cavity without water, and become solutions or suspensions, which in turn move to the absorption sites of the digestive system such as the oral cavity, esophagus, duodenum, small intestine, and the like. In clinical practice, it can be taken without water for a wide range of patients, such as elderly people and infants who have difficulty swallowing water or infants, so that they can improve their medication compliance and express their efficacy quickly and sufficiently. The FDA first defined orally disintegrating tablets (ODTs) in 1998 as 'solid medications' that quickly disintegrate in seconds when placed on the tongue. However, according to Guidance for Industry, Orally Disintegrating Tablets, published in December 2008, Orally disintegrating tablets (OTDs) are 'solid drugs containing drugs that disintegrate rapidly in the oral cavity and in the US Disintegration time is defined as less than 30 seconds when tested by the disintegration test listed in '.

Many researchers have developed various oral disintegrating tablets, which are classified into the following methods.

1. Lyphilization: The most representative of the lyophilization methods is the Zydis method. The solution or suspension containing the drug and excipients is quantitatively added to the tablet-shaped mold, followed by lyophilization to remove the solvent, leaving a solid in the shape of a mold. When water meets, it disintegrates and disperses in seconds. However, this technique requires expensive manufacturing equipment and a considerable time to manufacture once, and has a high demand for packaging due to its weak hardness and wear and tear. Commercially available formulations using this technology include Expidet, Lyoc, Rapidis, Wafer, Zofran Zydis.

2. Flashtab method: Flashtab method is a technology developed by Ethypharm, France. It uses solid dispersion technology to coat the drug particles with a coating base, for example, ammonia methacrylate copolymer (Eudragit). A tablet consisting of microparticles that is shielded and coated with an appropriate excipient in the coating process. When placed in the mouth, the tablet disperses into fine particles in 30 seconds without water. Commercially available oral disintegrating tablets using flashtab technology include Excedrin Quick Tabs, a combination product containing acetaminophen.

3. Spray dry method: The most representative method using the spray dry method is the WowTab technology of Yamanouchi Pharmaceutical Co., Ltd. in Japan. This is a tablet prepared by mixing a low-forming sugar and a high-forming sugar in an appropriate ratio, followed by spray drying with the drug. U.S. Patent No. 5,576,014 (Mizumoto et al.) And U.S. Patent No. 6,589,554 (Mizumoto et al.) Also relate to the technology of WoTab using a spray drying method.

4. Direct compression (direct compression) method: in which a foamable disintegrant and a tablet made by direct compression using a sweetener, Cima Labs, Inc. ORASOLV ^® technology, as described in (Wehling, etc.) U.S. Patent No. 5,178,878 Can be. Effervescent disintegrants include sodium bicarbonate, sodium carbonate, potassium bicarbonate and potassium carbonate, which are compounds that release carbon dioxide upon contact with water. The company also developed ORASOLV ^® technology to develop DURASOLV ^® technology, which provided stronger tablets for packaging in foil pouches or bottles, as described in US Pat. No. 6,024,981 (Khankari et al.). The main components of the tablets are non-direct compression fillers and sweeteners and lubricants. Non-direct compression fillers are very fine excipients, mainly dextrose, mannitol, sorbitol, lactose and sucrose. Non-direct compression filler is included in an amount of about 60-95% of the total tablet weight.

As described above, the manufacturing techniques of oral disintegrating tablets are various, but the porosity of the oral disintegrating tablets manufactured in general is designed to be higher in porosity and easier to penetrate water than conventional formulations. These tablets disintegrate quickly as water penetrates and disperses into tiny particles or becomes a solution. In the technology for preparing oral disintegrating tablets, the problem to be solved in the future is that the porosity is good while the hardness and wear resistance is good, and the disintegration, hardness and wear resistance are not affected by temperature and humidity when stored for a long time.

Granitacetic acid hydrochloride was first introduced in British Patent No. 2,125,398 as an antiemetic agent that suppresses nausea and vomiting that are common in chemotherapy. In modern medicine, early detection and treatment of cancer is an effective way to block cancer cells. However, one of the biggest side effects of chemotherapy or radiation therapy in chemotherapy is nausea and vomiting. This is because intestinal chromaffin cells secrete serotonin to stimulate 5-HT ₃ receptors during chemotherapy or radiotherapy, thereby triggering afferent secretion of the vagus nerve, resulting in vomiting. In order to reduce these side effects, new drug developments have been actively conducted to study anticancer adjuvants. In 1987, ondansetron, an antagonist of the first selective 5-HT ₃ receptor, was released. Subsequently many derivatives of ondansetron were released, and granisetron, an antagonist of the second more selective 5-HT ₃ receptor, was synthesized.

Granisseton hydrochloride has been marketed under the trade name Kytril as an injection. Currently, injections, tablets, and patches of granistron are marketed overseas. have. Injectable drugs, although fast in efficacy, require low doses for long-term chemotherapy. Commercially available tablets contain 1 mg of active ingredient per tablet, and chemotherapy adults take 1 to 2 tablets once or twice a day during chemotherapy, up to 9 mg daily. During radiotherapy, take 2 tablets once a day, up to 9 mg. Such conventional tablets are difficult to be frequently taken with water in the elderly and pediatric patients with poor swallowing ability and patients who are treated for long periods of time with nausea and vomiting.

The inventors of the present invention have provided a method for producing high purity granitone hydrochloride as well as economical under industrially simpler and milder reaction conditions than in the prior art in Korean Patent No. 522,392. Subsequently, the inventors have studied for many years suitable formulations of granisetron that are easy to take by chemotherapy patients. As a result, a suspension that not only has good porosity, hardness, and abrasion, but also masks the unique taste of granistron hydrochloride and quickly disintegrates in the oral cavity to form fine particles using a direct tableting method, which is the most convenient method of manufacturing. Or oral disintegrating tablets of granistron hydrochloride solution as a solution to come to complete the present invention.

Accordingly, it is an object of the present invention to provide orally disintegrating tablets of granisetrone or a pharmaceutically acceptable salt thereof.

Another object of the present invention is to provide a method for preparing orally disintegrating tablets of granisetrone or a pharmaceutically acceptable salt thereof.

The first aspect of the present invention

Granistron or particles thereof having a particle size of 50 μm or less as an active ingredient;

Sweeteners and flavoring agents;

Spray-dried lactohydrate, spray-dried D-mannitol or mixtures thereof as excipients;

Crospovidone with a particle size of 30 μm or less as a disintegrant;

Colloidal silicone dioxide as the first lubricant; And

Sodium stearyl fumarate as second lubricant:

It relates to the orally disintegrating tablet of granistron or a pharmaceutically acceptable salt thereof.

The second aspect of the present invention

Iii) grinding granisetron or a pharmaceutically acceptable salt thereof to a particle size of 50 μm or less, and then adding and mixing sweeteners and flavoring agents;

Ii) spray-dried lactohydrate, spray-dried D-mannitol, or a mixture thereof as an excipient is added to the mixture of step iii) and mixed;

V) adding first colloidal silicon dioxide to the mixture of step ii) for first utilization;

V) adding and mixing crospovidone with a particle size of 30 μm or less as a disintegrant to the mixture of step iv);

v) adding second sodium stearyl fumarate to the mixture of step iv) for a second lubrication;

Iii) directly tableting the mixture of step v):

It relates to a method for preparing orally disintegrating tablets of granistron or a pharmaceutically acceptable salt thereof, comprising the step.

The oral disintegrating tablet according to the present invention has a disintegration time of 30 seconds or less in vitro and rapidly disintegrates in the oral cavity, as well as masking the bitterness inherent in granitone, so that patients with swallowing disorders, especially those receiving long-term chemotherapy, The medication compliance is increased so that it can be taken without the need for expensive equipment, so it can be mass-produced in an economical and convenient way.

In the present invention, the water quickly penetrates into the tablet, quickly disintegrates into small particles, and the dispersed particles quickly become a solution. Particle size excipients, disintegrants and lubricants were selected and used to optimize the manufacturing process step by step.

Oral disintegrating tablet according to the present invention has the effect of rapidly disintegrating tablets through the following mechanism:

분무 Compared with conventional lactose hydrate or D-mannitol prepared by pulverizing sieve, spray-dried lactose hydrate or D-mannitol has high porosity and small and homogeneous particle surface. The particle size of the spray-dried lactohydrate or the spray-dried D-mannitol is preferably 300 μm or less, for example, 10 to 300 μm. In the present invention, after homogeneously dispersing granistron hydrochloride with spray-dried lactose or D-mannitol, the surface of the excipient is lubricated with colloidal silicon dioxide, which is a immersion-resistant lubricant, and water quickly penetrates into small particle surfaces. Do it.

⑵ As the disintegrant, crospovidone having a particle size of 30 µm or smaller, for example, 1 to 30 µm, smaller than that of a conventional disintegrant, is used to increase the relative distribution area during purification.

⑶ As the lubricant, sodium stearyl fumarate, which is more hydrophilic than magnesium stearate, which is a conventional lubricant, is used to improve the disintegration rate and dissolution rate.

Furthermore, the oral disintegrating tablet according to the present invention masks the intrinsic bitter taste of graniset hydrochloride by the following method:

그라 Graniscete hydrochloride with a particle size of 50 μm or less, for example 1 to 50 μm, is adsorbed on the surface of spray-dried lactose hydrate and D-mannitol surface, and colloidal silicon dioxide glides on the surface to give a bitter taste. Do not let granistron hydrochloride contact the tongue directly in the mouth.

⑵ Use a suitable amount of sweetener, flavor and D-mannitol in combination to ensure that the unique bitter taste of granitacetic acid hydrochloride is not detected in the oral cavity.

In the present invention, it is preferable that the amount of the spray-dried lactose hydrate as an excipient is 1 to 50% by weight, for example, 2 to 10% by weight based on the total weight of the tablet. The flowability and hardness are improved but the disintegration rate of the tablet can be lowered. The amount of spray-dried D-mannitol is preferably 10 to 70% by weight, for example 20 to 50% by weight, based on the total weight of the tablet.If the spray-dried D-mannitol is less than this, the tablets have a bitter taste and spray-dried D- If there is more mannitol, the disintegration rate may be lowered. As a disintegrant, crospovidone having a particle size of 30 μm or less is preferably used in an amount of 15 to 30 wt% based on the total weight of the tablet. If the amount of disintegrant is higher than this, the disintegration rate will not increase any more, and the residual feeling in the mouth will increase. Sweeteners and flavoring agents are suitably used in amounts of 0.1 to 5% by weight, respectively, based on the total weight of the tablet. Granisetrone or a pharmaceutically acceptable salt thereof is suitably used in an amount of 0.01 to 10% by weight based on the total weight of the tablet. Colloidal silicon dioxide and sodium stearyl fumarate are preferably included in an amount of 0.1 to 5% by weight based on the total weight of the tablet.

Hereinafter, the present invention will be described in more detail with reference to Examples, which are intended to aid the understanding of the present invention but are not intended to limit the scope of the present invention in any way.

Example 1 Granisetron Oral Disintegrating Tablet

7.819 g of granite hydrochloride, which was ground to a particle size of 50 µm or less, was mixed homogeneously with 7 g of peppermint flavor and 14 g of sweetener stevioside, and then mixed with 70 g of spray-dried lactose monohydrate in a 1: 1 dispersion. . 377.3 g of spray-dried D-mannitol was added thereto, mixed, and then 7 g of colloidal silicon dioxide was added and lubricated. Subsequently, 210 g of crospovidone having a particle size of 30 µm or less and 84 g of microcrystalline cellulose were mixed. After the mixture was sieved through No. 30, the mixture was lubricated again with 7 g of sodium stearyl fumarate, and tableted to include 1.117 mg (1 mg as granistron) per tablet. The amount of each component per unit tablet is shown in Table 1 below.

Composition of tablets Example 1  Mg / tablet Weight percent per tablet Graniset hydrochloride      1.117    1.00 Peppermint Bee 5010  One    0.89 Stevioside  2    1.79 Spray-Dried Lactose Carb 10    8.93 Spray dried mannitol   53.9    48.12 Microcrystalline cellulose 12    10.71 Crospovidone (30 μm or less) 30     26.78 Colloidal silicon dioxide  One      0.89 Sodium stearyl fumarate  One      0.89 Sum    112.017 100

Example 2: Granisetron oral disintegrating tablet preparation

7.819 g of granise hydrochloride, which was ground to a particle size of 50 µm or less, was mixed homogeneously with 7 g of vanilla flavor and 14 g of sweetener stevioside, and then mixed with 175 g of spray-dried lactose monohydrate in a 1: 1 distribution. . 377.3 g of spray-dried D-mannitol was added thereto, mixed, and then 7 g of colloidal silicon dioxide was added and lubricated. Subsequently, 210 g of crospovidone having a particle size of 30 µm or less were mixed. After the above mixture was sieved through No. 30, the mixture was lubricated again with 7 g of sodium stearyl fumarate, and the mixture was mixed so that 1 mg of granisetone hydrochloride (1 mg as granisetrone) was contained per tablet. Tablets were prepared using a rotary tablet press (MRC-33, Sejong Pharmatech) under pressure conditions of 3.0 to 6.0 kN, thickness 3.0 to 4.0 mm, and rotation speed of 50 rpm. To maintain the hardness of 3.5 to 6.5 kp to tablet as possible. The amount of each component per unit tablet is shown in Table 2 below.

Composition of tablets Example 2  Mg / tablet Weight percent per tablet Graniset hydrochloride      1.117   0.97 Vanilla flavoring  One   0.87 Stevioside (sweetener)  2   1.74 Spray-Dried Lactose Carb 25    21.74 Spray dried mannitol   53.9    46.86 Crospovidone (30 μm or less) 30     26.08 Colloidal silicon dioxide  One      0.87 Sodium stearyl fumarate  One      0.87 Sum    115.017 100

Comparative example:

As shown in Table 3 below, tablets were prepared by directly tableting a mixture of 100 tablets.

Composition of tablets Comparative example  Mg / tablet Weight percent per tablet Graniset hydrochloride     1.117      0.89 Sodium bicarbonate 7      5.59 Spray-Dried Lactose Carb   46.5     37.17 White sugar 20     15.99 Microcrystalline cellulose 20     15.99 Crospovidone 30     23.98 Magnesium stearate    0.5     0.4 Sum    125.117 100

Experimental Example:

The following items were evaluated about the tablet obtained by the said Example 1 and the comparative example.

1. Disintegration test: In accordance with the US Pharmacopoeia Disintegration Test method, using a 37 ° C water as the disintegration test solution, one specimen was put in six glass tubes of tester, and the tester was operated. The time at which no residue of the sample remained was measured as the disintegration time.

2. Hardness test: The hardness of each tablet was measured by a hardness tester (ERWEK), the test was repeated 10 times to obtain the average value.

3. Measurement of wear and tear: Wear and tear was measured using a wear tester.

4. Sensory test: Measured granny seton oral disintegrating tablet in the mouth of 10 adults and measure the unique bitterness shielding of granistetron and the residual feeling when tablets disintegrate completely in the mouth through sensory test. It was. In the sensory test, the 5-point method was used.

[Bitter Tightness]

5 points-very good; 4 points-good; 3 points-moderate; 2 points-bad; 1 point-very bad

[Residual feeling]

5 points-very good (no residue at all); 4 points-good (no residue); 3 points-moderate (with little residual; or acceptable); 2 points-poor (remaining feeling); 1 point-Very poor

The results are shown in Table 4 below.

 Evaluation item Example 1  Comparative example Disintegration time (n = 6) 15 seconds or less More than 1 minute Longitude (n = 10) 4.2 kp 4 kp Masson 0.02% 0.05% Taste shielding degree (n = 10) 4.3 1.0 Residual (n = 10) 4.3 2.0

Claims (9)

Granistron or particles thereof having a particle size of 50 μm or less as an active ingredient; Sweetening and flavoring agents; Spray-dried lactohydrate, spray-dried D-mannitol or mixtures thereof as excipients; Crospovidone with a particle size of 30 μm or less as a disintegrant; Colloidal silicon dioxide as the first lubricant; And Sodium stearyl fumarate as second lubricant: Including oral disintegrating tablets of granistron or a pharmaceutically acceptable salt thereof. The method of claim 1, Iii) grind grannistron or a pharmaceutically acceptable salt thereof to a particle size of 50 μm or less, and then add sweetener and flavoring agent to mix; Ii) spray-dried lactohydrate, spray-dried D-mannitol, or a mixture thereof as an excipient is added to the mixture of step iii) and mixed; V) adding first colloidal silicon dioxide to the mixture of step ii) for first utilization; V) adding and mixing crospovidone with a particle size of 30 μm or less as a disintegrant to the mixture of step iv); v) adding second sodium stearyl fumarate to the mixture of step iv) for a second lubrication; Iii) directly tableting the mixture of step v): An orally disintegrating tablet of granisetrone or a pharmaceutically acceptable salt thereof prepared by the method comprising the step. The orally disintegrating tablet of granistrone or a pharmaceutically acceptable salt thereof according to claim 1, wherein the particle size of the spray-dried lactohydrate or the spray-dried D-mannitol is 300 µm or less. The granitone according to claim 1, which comprises 1 to 50% by weight of spray-dried lactose hydrate and 10 to 70% by weight of spray-dried D-mannitol, based on the total weight of the tablet. Oral disintegrating tablets of salts. The orally disintegrating tablet of granistron or a pharmaceutically acceptable salt thereof according to claim 1, comprising 15-30% by weight of crospovidone, based on the total weight of the tablet. The orally disintegrating tablet of granisetrone or a pharmaceutically acceptable salt thereof according to claim 1, comprising 0.1 to 5% by weight of sweetener and flavoring agent, respectively, relative to the total weight of the tablet. The orally disintegrating tablet of granisetron or a pharmaceutically acceptable salt thereof according to claim 1, which comprises 0.01 to 10% by weight of granistron or a pharmaceutically acceptable salt thereof, based on the total weight of the tablet. The orally disintegrating tablet of granisetron or a pharmaceutically acceptable salt thereof according to claim 1, comprising 0.1 to 5% by weight of colloidal silicon dioxide and sodium stearyl fumarate, respectively. Iii) grind grannistron or a pharmaceutically acceptable salt thereof to a particle size of 50 μm or less, and then add sweetener and flavoring agent to mix; Ii) spray-dried lactohydrate, spray-dried D-mannitol, or a mixture thereof as an excipient is added to the mixture of step iii) and mixed; V) adding first colloidal silicon dioxide to the mixture of step ii) for first utilization; V) adding and mixing crospovidone with a particle size of 30 μm or less as a disintegrant to the mixture of step iv); v) adding second sodium stearyl fumarate to the mixture of step iv) for a second lubrication; Iii) directly tableting the mixture of step v): A method for preparing orally disintegrating tablets of granistron or a pharmaceutically acceptable salt thereof, comprising the step of: