Tablet is a traditional dosage form. Due to its stable quality, accurate dosage, convenient taking, easy to carry, high degree of mechanization and low production cost, it has become one of the commonly used dosage forms. However, due to the pressure molding of tablets, the disintegration is slow. Bioavailability is low and some patients have difficulty swallowing, so the use of tablets may be limited to some extent. For this reason, oral solid immediate release preparations have become a hot spot in the development of new drugs in recent years. Dispersible tablets, chewable tablets, orally disintegrating tablets, oral immediate release tablets, oral instant tablets, self-emulsifying drug delivery systems, sublingual tablets, etc. are constantly emerging. In particular, orally disintegrating tablets have become the focus of tablet development because of their convenience in taking, fast onset, high bioavailability, and good taste.
1, the concept of orally disintegrating tablets
Orally disintegrating tablets refer to tablets that do not need water or only need a small amount of water, do not need to chew, the tablets are placed on the tongue, and after the saliva is quickly dissolved or collapsed, the drugs can be put into the stomach by swallowing power.
Because of its rapid disintegration or deep solution in the oral cavity, it is currently confused. Its naming includes: orally dissolving tablets; fast-dissolving tablets, fast dissolving tablets (fast dissolving tablets), fast dissolving drug form (FDDF); rapidly disintegraring tablets; Quick-liquifying chewable tablets and the like. In addition, there are also applications for the registration of new drugs, such as immediate release tablets, oral instant tablets, or oral disintegrating tablets. In the appendix of the second edition of the Chinese Pharmacopoeia 2000, there are the release of the instant release tablets. Therefore, some manufacturers declare the name of "×××immediate release tablets", and later merchants import them with the name of "×××oral instant tablets". Drug registration declaration. In response to the confusing phenomenon, the National Drug Evaluation Center specially organized experts to argue that "immediate release tablets" have been included in the appendix of the Chinese Pharmacopoeia 2000 edition, but did not specify clear technical requirements. Considering that there are no overseas release tablets listed at present, it is still impossible to learn from foreign materials; at the same time, lack of support from domestic materials, the technical requirements are not mature enough, and there is no real instant release report in China, so the release tablets are available. The technical requirements are not clear and open for the time being. After the time is ripe, further discussion and determination will be made. The oral instant tablets are not listed in foreign countries. The domestic new drug declarations are misunderstood and translated, so the new formulation name will not be recognized for the time being. Caused by confusion of management and orientation; therefore, the National Drug Evaluation Center will define tablets that rapidly disintegrate (or dissolve) in the mouth, which are uniformly defined as "Orally disintegrating tablets".
2. Technical requirements and characteristics of orally disintegrating tablets
(1) Technical requirements for orally disintegrating tablets
In May 2002, the National Drug Testing Center's technical requirements for orally disintegrating tablets were as follows:
1 should be rapidly disintegrated in the oral cavity, no gritty, good taste, easy to swallow, no irritation to the oral mucosa, and set the quality standard neutral item.
2 Establish appropriate methods and limits for the determination of disintegration time limits and set the standards.
3 For poorly soluble drugs, appropriate dissolution methods and limits should be established and quality standards should be established.
(2) Characteristics of orally disintegrating tablets
1 fast absorption, high bioavailability: orally disintegrating tablets can affect the dissolution rate of the drug, especially the dissolution rate of the insoluble drug, so the orally disintegrating tablet can improve the bioavailability of the drug; small dose or molecular weight Small water-soluble drugs, such as pH-adjusting the presence of the drug in non-ionic form in the oral cavity, can also increase its bioavailability. Therefore, oral disintegration tablets are suitable for drugs that require rapid onset and have a large difference between effective concentration and poisoning concentration. Some war wounds, non-steroidal anti-inflammatory drugs, antispasmodic antiemetics and analgesics are all It is more suitable for making orally disintegrating tablets; other drugs such as blood drug concentration are relatively stable in the long-term, it is easy to produce drug resistance, after making an orally disintegrating tablet, it can overcome this problem and produce good therapeutic effect.
2 convenient to take: Oral disintegrating tablets do not need to be taken with water, saliva can be disintegrated or dissolved, can be swallowed according to common agents, can be placed in water after disintegration and delivery, can also be swallowed without taking water. It is especially suitable for the elderly, children with dysphagia and those who are inconvenient to take medicine. If a certain method is used to improve the taste of the preparation during preparation, the medication compliance of the child patient can be greatly improved, and the problem of difficulty in taking medicine for infants and children can be solved.
3 less intestinal residue, low side effects: such as piroxicam fast-acting tablets have lower gastrointestinal reaction rate than diclofenac and naproxen tablets. The antipyretic analgesic aspirin and ibuprofen avalanche tablets can rapidly disintegrate and disperse into fine particles before the drug reaches the gastrointestinal tract, causing the drug to be distributed in a large area of ​​the gastrointestinal tract, and the absorption point is increased, thereby reducing The local stimulation of the drug to the gastrointestinal tract.
4 to avoid the first pass effect of the liver: due to the rapid disintegration of the orally disintegrating tablet in the mouth, in addition to most of the swallowing action into the gastrointestinal tract, a considerable part of the oral absorption, so the effect is fast, the first pass effect is small.
5 local treatment: ordinary oral solid preparations reach the bottom of the stomach and quickly empty, it is difficult to achieve the targeted effect of the stomach. An orally disintegrating tablet containing an anion exchange resin is uniformly dissolved in the stomach due to its dissolution in the oral cavity, and 10% of the drug is retained in the stomach for 5.5 hours, and the Helicobacter pylori can be locally treated.
6 rapid development: from effervescent tablets to solution tablets, dispersible tablets, sublingual tablets and buccal tablets, each has its own advantages and disadvantages, to be improved. With the development of spray drying technology, solid solution technology and full-powder direct compression technology and the development of excellent excipients, orally disintegrating tablets have developed rapidly with their unique characteristics. At present, many research units in China are still developing such varieties in large quantities.
3. Common techniques for preparing orally disintegrating tablets
1 spray drying process: adding static-charged polymer, solubilizer, expansion agent, etc. to ethanol, buffer, etc., by spray drying method to obtain porous particles as a support skeleton of the tablet, the polymer in the skeleton The static charge is directly compressed with a solubilizing agent and a swelling agent, a filler, a flavoring agent, etc., and a film coating may be applied after the Zui. Therefore, after the orally disintegrating tablet made by this technology encounters saliva, the moisture can quickly enter the inner core of the tablet, and immediately disintegrates due to the rejection of the same static charge in the particles, generally about 20 seconds.
2 Direct compression method: As a common process for preparing orally disintegrating tablets, MCC with strong compressibility and disintegration is used as a filler, and a disintegrating agent with strong disintegration performance, such as CMCNa, is added. Direct compression of cross-linked PVP, cross-linked Ca, L-HPC and agar treatment allows the tablet to disintegrate in a short time. BI or the like uses 80% to 90% microcrystalline cellulose MCC (Avicel PH102) and low-substituted hydroxypropyl cellulose (L-HPC, LH-11) to prepare an orally disintegrating tablet, which can be completely disintegrated within 10 seconds. Watanabe et al. prepared an orally disintegrating tablet by MCC (commodity Avicel PH301): L-HPC (LH-11) 8:2, tableting force 0.98×103 to 2.94×103 N, and was substantially completely disintegrated in 5 seconds.
3 pretreatment method: In order to solve the problem that the orally disintegrating tablet has a gritty feeling, the drug can be first wrapped into a micron-sized small or high-molecular polymer (gelatin, cellulose, acrylic polymer or ethylene copolymer). Granules to improve the bad taste of the drug, add 60% to 95% (v / v) of non-direct compression tablet filler (such as mannitol, sorbitol, etc.), then add effervescent, moisture, flavor Mix for 30~50 minutes, add 1.5%~2% lubricant evenly, then mix for 5~10 minutes. The orally disintegrating tablet can be completely disintegrated in 40 seconds, and the hardness and friability are qualified, and the mouthfeel is good (the mannitol absorbs heat when it is dissolved, and the taste is cool).
4 flash flow technology: Fuisz uses flash heat and flash shear technology to make carrier materials such as glucose and sucrose into a rod-shaped shear skeleton structure. At this time, the carrier material is amorphous. The form exists, and then under the action of the crystallization initiator, the shearing skeleton and the addition of the flow aid form a fine particle which is suitable for direct compression, and then presses with a small tableting force to achieve instant dissolution in the mouth. the goal of.
5 Other technologies: At present, solid solution technology and freeze-drying technology are also used in the world for the development of orally disintegrating tablets. The solid solution technology uses two solvents, completely dissolves the carrier material with * kinds of solvents, and then adds the second type after freezing. The solvent is replaced by a solvent to obtain a carrier skeleton having a high porosity, and after being solidified by a certain method, it is directly compressed. In addition, it can also be used after wet granulation and tableting. However, it has been found that the wet granulation method has a significant effect on the disintegration time limit, and the tablets prepared by the spheronization granulation method have a disintegration time compared with the granules of the swaying granule mechanism. Much shorter.
4, accessories
The key to preparing an orally disintegrating tablet is to find a suitable excipient to ensure good fluidity under pressure, strong compressibility, and rapid disintegration. In addition, the tablet is required to have a good mouthfeel. Commonly used excipients are: croscarmellose sodium (CCMSa), croscarmellose sodium (CCMS-Na), cross-linked polyvinylpyrrolidone (PVPP), microcrystalline cellulose (MCC), low-substituted carboxy-propyl Cellulose (L-HPC) and treated agar (TAG), gelatin, mannitol, lactose, and the like.
1 croscarmellose sodium (CCNa), cross-linked polyvinylpyrrolidone (PVPP), croscarmellose sodium (CCMS-Na): CCNa is highly swellable but insoluble in water, with excellent disintegration . Fererro and other water-insoluble drugs, citrate protein, were used as model drugs for direct compression. The results showed that the CCNa content was 5%~10%, and the tableting pressure was 250~280MPa. The disintegration time was only ten seconds. If there is no CCNa in the prescription, it will not disintegrate within 30 minutes. Lin Wenhui and other calcium orally disintegrating tablets made of CCNa and CCMS-Na can be disintegrated completely within 45 seconds. Polyvinylpyrrolidone is insoluble in water, has strong hygroscopicity and is weak in swelling. The PVPP disintegration effect is good. CCMS-Na has good water absorption and water swelling. After fully expanding, the volume can be increased by 200~300 times, and has good compressibility. It is often used for direct compression, which can improve the formability of the tablet and increase the hardness of the tablet without affecting its disintegration. The dosage is generally 4 %~8%.
2 Weichang cellulose (MCC): MCC is an excipient currently used in Zuiguang, which has a sponge-like porous tube structure. When pressed, the porous structure of MCC is linearly arranged by disorder, and plastic deformation, so that MCC can be pressed, and it is suitable for direct compression, and its dosage can reach 80%~90%. Because it has a weak swelling property, it is generally not used as a disintegrating agent alone, and is often used in combination with other exuding agents such as L-HPC, and the obtained tablet can be disintegrated within 10 seconds.
3 low-substituted hydroxypropyl cellulose (L-HPC): L-HPC has strong hygroscopicity and swells in water without dissolving. In addition, L-HPC has a rough surface structure, which enhances the mosaic effect between the powder and the particles, and improves the viscosity and smoothness of the tablet. Therefore, the use of L-HPC as an auxiliary material can play a dual role of disintegration and bonding, and the dosage is generally 2% to 5%. Wa-tanabe et al. used direct compression method, combined with the good compressibility of MCC and the obvious swelling property of L-HPC, and the two were used together as a disintegrant, and the orally disintegrating tablet was prepared to disintegrate within 5 seconds.
4 treatment of agar (TAC): agar swells at room temperature but does not turn into a gel. Ito et al. found that agar under water swells at room temperature and then dried, and the prepared TAG has good disintegration properties. It can be used for the preparation of orally disintegrating tablets, which is determined by the swelling action of TAG. . When the swollen agar is dried, the water evaporates from the agar, so that the rapid rupture of the formed TAG is due to its large pore size and total pore volume, which enables rapid penetration of water and accelerates disintegration.
5 Other excipients: Since the orally disintegrating tablet rapidly disintegrates into fine particles in the oral cavity, it is necessary to pay attention to the taste problem when preparing the orally disintegrating tablet. Bi et al. prepared a good effect by preparing an orally disintegrating tablet by using α-lactose-hydrate (TT) which has good fluidity and compressibility instead of α-lactose. In order to overcome the gritty feeling of the orally disintegrating tablets, Koizumi et al. used mannitol as a filler, mixed with camphor and heated to make the camphor sublimate, and obtained a tablet having a porosity of 20% to 30%, and mannitol was completely dissolved in the mouth. The taste is very good. Bi and the like use 50% tetrahydrofuran (ET) as a filler, which can basically overcome the sand sensation. And ET taste cool and hardness, has little effect on disintegration. At present, mannitol and lactose are mainly used as fillers in China, and at the same time, it is the main auxiliary material for improving taste.
5, the problem of oral disintegration tablets and solutions
1 Dose problem of the drug: Since the orally disintegrating tablet requires rapid disintegration, it also needs a good mouthfeel, so a large amount of excellent disintegrant and flavoring agent are added during tableting, and the obtained tablet weight and tablet are obtained. If the type is too large, it is inconvenient to take, so the dosage of the drug is required to be small. Therefore, the drug requirements for the development of orally disintegrating tablets are high-efficiency, low-dose drugs.
2 The problem of the taste of the drug: Since the orally disintegrating tablet is released in the oral cavity, the bitterness of the drug or the irritating taste is not suitable for the preparation, especially for the bitter-tasting drug, only the fragrance or flavor is added. The agent is not enough to improve the taste. Lshikawa et al. mixed the drug with the resin and made it into granules to cover up the bitter taste of the drug. Pfizer Cima uses a polymer material for microencapsulation or granulation, and then coats it with a polymer material to provide a good taste-masking effect.
3 Preparation process problems: Previously, orally disintegrating tablets were commonly used in freeze-drying, spray drying, etc. Some processes require many steps, take a long time, and some also need to use organic solvents, etc., resulting in a series of labor protection and environmental pollution problems. The cost of the orally disintegrating tablet is greatly increased, which limits the development of such a dosage form. Due to the development of excipients, it is possible to directly compress the powder, which is of great significance for the development of such pharmaceuticals.
6 Conclusion
The development of orally disintegrating tablets has opened up new avenues for emergency treatment, and also provides a new method for the oral absorption of poorly soluble drugs, which is suitable for elderly and children, especially for cancer chemotherapy patients who swallow water and vomit. The words have more advantages in use, thus finding a solution to improve the quality of life of patients; in addition, it provides convenience for the special situation of medical services such as geological workers with inconvenient drinking water in the field and desert areas, and also solves the previous tablets. The lack of disintegration provides new ideas. The promotion of orally disintegrating tablets will not only promote the reform of tablet preparation, but also cause a huge revolution in pharmaceutical technology, auxiliary materials production and clinical drug use. It is of epoch-making significance in the innovation of drug use, and will certainly create a huge economy and society. benefit.
Source: Compilation of pharmaceutical industry information
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