Selection of excipients in freeze-drying method The formula of freeze-dried instant tablets includes main medicine, matrix and other excipients, and the preparation has a certain shape and strength after freeze-drying. In order to make the freeze-dried tablets brittle and porous, a certain amount of bubbles must be kept in the drug solution or suspension, and the key to preparation is to take/quickly freeze them first. Secondly, one or more surfactants can be added to the drug solution, and the surfactant is sodium dodecyl sulfate! Lecithin! Twain and Span, etc. In order to make the drug evenly distributed in the suspension, a certain amount of long-chain macromolecules, such as peptides (gelatin or dehydrated gelatin), can be added; Polysaccharides (dextran, dextran, mannitol and starch, etc. ); Gum (Arabic gum, xanthan gum and gum), cellulose, alginate, PVP, polyvinyl alcohol, etc. , can also keep small bubbles.
Other auxiliary materials can be added according to the needs of different prescriptions, such as wetting agent (ethanol), coloring agent (iron oxide), preservative, antioxidant, perfume, etc.
Preparation technology The principle of preparing instant tablets by freeze-drying method is a drying method that the drug is quickly frozen into a solid after being made into a suspension, and then directly sublimated under vacuum to remove the water in the frozen state. Freeze-dried products are generally loose in structure and rich in tiny gaps, which can quickly absorb water and dissolve. By accelerating the freezing speed, the crystal lattice arrangement of some drugs can be changed during recrystallization, so that the crystal particle size is reduced and the specific surface area is increased, or some drugs are in a high-energy metastable or amorphous state, both of which increase the solubility and dissolution rate of drugs. These characteristics of freeze-drying are used to prepare quick-acting oral soluble tablets and quick-release tablets. Wong et al [9] chose xanthan gum! Famotidine oral soluble tablets were prepared by freeze-drying technology with gelatin and mannitol as main raw materials.
At present, it is reported that phenylpropanolamine hydrochloride, oxazepam, lorazepam, nitroglycerin, isosorbide dinitrate, nifedipine and difenidol hydrochloride are used to prepare oral soluble tablets, while meclozine hydrochloride, oxazepam and difenidol hydrochloride are used to prepare instant tablets. Sam et al. [16] prepared hydrochlorothiazide oral instant tablets according to freeze-drying technology. With xanthan gum, gelatin and polyethylene glycol 6000 as matrix and auxiliary materials, xanthan gum as suspending agents and PVC blister as molding materials, Zydis, a new quick-dissolving dosage form, was developed. The dosage form can be disintegrated in a small amount of water or tongue within 10s, and is mainly used for tablets or tablets. Merck [12] marketed famotidine orally soluble tablets with Zydis rapid solvent preparation technology, and the price was the same as that of ordinary preparations. There is no such new dosage form in China.
In the process of spray drying, ethanol and buffer solution were added to the polymer, solubilizer and swelling agent containing electrostatic charge, and porous particles were prepared by spray drying method as the supporting skeleton of tablets. The electrostatic charge of the polymer in the skeleton was the same as that of the solubilizer and swelling agent. Then adding drugs, adhesives, fillers, flavoring agents and the like. Or finally coating with a film coating. Therefore, after the orally disintegrating tablet made by this technology meets saliva, water can quickly enter the core of the tablet and disintegrate immediately, generally about 20 seconds, due to the repulsive effect of the same-sex electrostatic charge in the particle. As a common process for preparing orally disintegrating tablets, MCC with strong compressibility and disintegration is often used as filler, and then disintegrants with strong disintegration, such as CMCNa, cross-linked PVP, cross-linked CMSNa, L-HP and treated agar, are added for direct tabletting, so that the tablets can disintegrate in a short time.
Powder direct compression method is low in cost, simple in technological process, energy-saving and time-saving, which is beneficial to continuous and automatic production of tablets. Microcrystalline cellulose (MCC) with strong compressibility and disintegration is often used as a filler and disintegrant with strong disintegration, such as CCNa and cross-linked polyvinylpyrrolidone (PVPP), which makes tablets disintegrate in a short time.
New excipients: acetaminophen or vitamin C orally disintegrating tablets are made of spherical microcrystalline cellulose [Avicel PH-M series, particle size 7 ~ 32 microns] and low-substituted hydroxypropyl cellulose L-HPC(9∶ 1); Shu et al. grinded 30%(w/w) D- mannitol and the physical mixture of (9∶ 1), mannitol 65.5%, 4% and magnesium stearate 0.5% to prepare orally disintegrating tablets with hardness of 4.9kg and disintegration time of 33 s. The experimental results showed that the physical mixture of mannitol and mannitol was harder than that when used alone, which was more in line with oral disintegration. Ishikawa et al. used Eudragit E- 100 as the corrective, made drug granules by extrusion method, and then added excipient (MCC-L-HPC, 8∶2) to make orally disintegrating tablets.
At present, orally disintegrating tablets generally have the problems of low physical strength, high brittleness and inconvenient transportation and storage. In order to improve the mechanical integrity and tensile strength of orally disintegrating tablets, Sugimoto and others used amorphous sucrose and mannitol as excipients to directly compress orally disintegrating tablets with high porosity and good permeability. Thermal analysis and powder X-ray diffraction show that amorphous sucrose is transformed during storage, forming solid bridges in tablets and becoming new internal contact points. Amorphous sucrose is closely combined with mannitol, and the tensile strength of tablets increases. This crystal transformation method is an effective method to improve the mechanical strength of orally disintegrating tablets. Bi et al. used microcrystalline cellulose, tablets, CCNa(Ac-di-sol) or erythritol to prepare orally disintegrating tablets. The orally disintegrating tablets optimized by response surface and contour maps have sufficient tensile strength and good taste. In order to solve the problem that orally disintegrating tablets feel gritty, natural or synthetic polymers (gelatin, cellulose, acrylic polymer or ethylene polymer, etc.) can be used to wrap drugs into micron-sized particles. ) to improve the bad taste of drugs, and 60%~95%(vPv) of indirect tablet fillers (such as mannitol and sorbitol, etc. ) can be added, and then effervescent agent, hygroscopic agent and flavoring agent can be added. The orally disintegrating tablets can be completely disintegrated within 40 seconds, and the hardness and brittleness are qualified, and the taste is good (mannitol absorbs heat when dissolved, and the taste is cool).
Flash technology fuisz Company uses flash heat and flash shear technology to make carrier materials such as glucose and sucrose into rod-shaped shear skeleton structure, at this time, the carrier materials exist in amorphous state, and then under the action of crystallization initiator, shear skeleton and glidant are added to form fine particles with good fluidity, which are suitable for direct tabletting, and then tabletting with small tabletting force to achieve the purpose of instant oral dissolution. At present, solid solution technology and freeze-drying technology are also used in the development of orally disintegrating tablets in the world. The solid solution technology uses two solvents, the first solvent is used to completely dissolve the carrier substance, the second solvent is added after freezing to replace the first solvent, and then the second solvent is volatilized by an appropriate method to obtain the carrier skeleton with high porosity, which is obtained by direct tabletting after curing by a certain method. In addition, there are tablets made by wet granulation, but it is found that the wet granulation method has a very significant impact on the disintegration time. The disintegration time of tablets made by rolling granulation method is much shorter than that of tablets made by swing granulator.
The main drug has poor fluidity and large dosage, so wet granulation and tabletting can be used. The preparation method is the same as that of ordinary tablets, and the disintegration time and dissolution rate of the prepared orally disintegrating tablets meet the requirements. It shows that qualified orally disintegrating tablets can be obtained by using the existing domestic equipment, suitable excipients and technology. Abdelbary et al. used hydrophilic wax material PEG-6- stearate (trade name: Superpolystate, PEG-6- stearate, MP33 ~ 37℃, HLB value: 9) as binder to granulate and press orally disintegrating tablets.
Ultra-poly-L-lysine can not only be used as an adhesive to increase the physical tension of orally disintegrating tablets, but also can be quickly dissolved in the mouth, which is helpful for the disintegration of orally disintegrating tablets.
Ultra-poly-lysine can be prepared by two different granulation methods: wet granulation, that is, granulation with o/w emulsion formed by this waxy substance and distilled water as binder;
Melt granulation, that is, keep the granulation temperature at (42 2)℃ and make it in a molten state as a binder.
In the experiment, acetaminophen was used as a model drug and D- mannitol was used as an excipient. The particle size distribution obtained by the two methods was compared by laser diffraction, and its morphological characteristics were detected by scanning electron microscope. The possibility of adding cross-linked sodium carboxymethyl cellulose (CCNa) as disintegrant was also evaluated. It was found that adding 2%(w/w) CCNa as disintegrant can greatly shorten the disintegration time without affecting the hardness and brittleness of tablets. Results the tablets prepared by the two granulation methods have good hardness and are not easy to embrittle. With this material, orally disintegrating tablets with hardness of (47.9 2.5) N and disintegration time of (40 2) s can be prepared.
In the literature, orally disintegrating tablets were prepared by wet pressing method with lactose as excipient and water as wetting agent. The obtained wet granules were directly tabletted, and the obtained wet tablets were dried at 60℃ for 3 hours. The properties of orally disintegrating tablets can be determined after they are placed at room temperature for 12h. The tensile strength of orally disintegrating tablets prepared by the optimized process is greater than 0.5MPa, and the disintegration time is less than 30s, all of which meet the requirements. However, it is difficult to control the moisture content in wet granules before tabletting, and it is easy to stick when tabletting, which is difficult to operate and needs further study. This method mainly uses two solvents. The first solvent completely dissolves the carrier substance, after freezing, the second solvent is added to replace the first solvent, and then the second solvent is volatilized by a certain method to obtain the carrier skeleton with high porosity. The selection of solvent, carrier and drug is very strict, which generally meets the following conditions: there is no interaction between drug, solvent and carrier. The freeze point of that second solvent is higher than that of the first solvent. The drug and carrier are soluble in the first solvent, but insoluble in the second solvent. The industrial production of this process is difficult and the cost is too high. If organic solvents are used, solvent residues and safety issues cannot be ignored.
Spray drying process: the polymer contains electrostatic charge, solubilizing agent, swelling agent and so on. Adding ethanol and buffer solution, and spray drying to obtain porous particles. Then, drugs and other auxiliary materials are added, and the instant tablets are made by common tabletting technology. When the tablet meets saliva, the tablet disintegrates rapidly due to the electrostatic charge between the particles.
condiments
The key to the preparation of orally disintegrating tablets is to find suitable excipients to ensure good fluidity, strong compressibility and rapid disintegration under pressure. In addition, the prepared tablets are required to have a good taste.