Water-free oral granule is a solid dosage form that can be rapidly disintegrated or dissolved in the oral cavity without water, and can directly enter the gastrointestinal tract to exert its efficacy through swallowing. The dosage form is especially suitable for the elderly, children, patients with dysphagia and people in special environments (such as water-deficient areas, outdoor work, etc.). Compared with traditional tablets, capsules and other dosage forms, water-free oral granules greatly reduce the patient's resistance to taking medicine due to swallowing difficulties and improve the patient's compliance; Compared with oral liquid preparation, it has the advantages of convenient storage, transportation and higher stability. In recent years, with the cross-innovation of material science and preparation engineering, the technology platform has made breakthrough progress in drug taste masking, stability control and industrial production.
First, Core structure design of water-free oral granules.
Water-free oral granules usually adopt a double-layer structure of "taste-masking pellets+taste-correcting matrix". Taking azithromycin anhydrous swallowing taste masking particles as an example, the taste masking layer is composed of ethyl cellulose and triethyl citrate, and a dense film layer is formed by electrostatic spraying technology to block the bitterness of the drug; The corrective matrix is composed of mannitol and L- menthol to cover up the residual odor through the cool feeling of the mouth. This design realizes the dual mechanism of "physical taste masking+chemical taste correction", which significantly improves the patient's medication compliance. It is true that the development of this mechanism is inseparable from the innovation of excipients. What technological innovations have been brought by water-free oral granules in the application of excipients?
Mainly include: disintegration accelerator: the dosage of cross-linked povidone K-30 should reach 200% of the active ingredient, and form a porous skeleton structure with starch, so that the particles can quickly absorb water and expand in saliva. For example, by controlling the ratio of cross-linked povidone K-30 to starch, aspirin anhydrous swallowing granules achieved complete disintegration within 5 seconds. Stabilizer system: the composite matrix of magnesium aluminum silicate and erythritol is adopted, so that lactic acid bacteria particles can carry bacteria stably. The system can prolong the life cycle of probiotics by absorbing water and inhibiting oxidation reaction.
Second, the preparation technology of water-free oral granules
Direct tabletting method: after the drugs are mixed with appropriate excipients (such as fillers, disintegrants, lubricants, etc.), they are directly tabletted and made into granules. This method has simple operation and high production efficiency, but it requires high fluidity and compressibility of materials. For example, microcrystalline cellulose as filler can not only increase the volume of materials, but also improve the compressibility of materials; Cross-linked povidone, as a disintegrant, can quickly absorb water and expand in oral saliva environment, and promote the disintegration of particles.
Wet granulation method: firstly, the medicine and auxiliary materials are evenly mixed, and a proper amount of adhesive is added to make soft materials, and then wet granules are made by granulation equipment (such as swing granulator, fluidized bed granulator, etc.), and water-free oral granules are obtained after drying and grading. In this process, the choice of adhesive is very important, and the commonly used adhesives are povidone aqueous solution, hydroxypropyl methylcellulose aqueous solution and so on. Wet granulation can make the granules have good formability and stability, but the energy consumption in drying process is high, and the granulation process may affect the stability of drugs.
Spray drying method: Dissolve or disperse drugs and auxiliary materials in a suitable solvent to make a uniform solution or suspension, and spray it into the drying room through a spray device. Under the action of hot air flow, the solvent quickly evaporates to form fine particles. The particles prepared by spray drying method have the advantages of uniform particle size, large specific surface area and fast dissolution rate, and are especially suitable for drugs sensitive to damp heat. However, this method has large equipment investment and high requirements for production process control.
Freeze-drying method: the drug solution or suspension is pre-frozen to make it freeze into solid state, and then the water is removed by sublimation under high vacuum to obtain loose and porous particles. Freeze-drying method can retain the active ingredients of drugs to the maximum extent, and the prepared particles have excellent disintegration and dissolution performance, but the production cost is high and the production cycle is long.
Third, the key technical points of water-free oral granules
① Optimization of disintegration and dissolution performance: In order to realize rapid disintegration and dissolution of water-free oral granules in the oral cavity, it is necessary to reasonably select disintegrants and dissolution promoters. In addition to the aforementioned cross-linked povidone, sodium carboxymethyl starch and low-substituted hydroxypropyl cellulose are also commonly used disintegrants, which can accelerate the disintegration of particles through capillary action and water absorption and expansion. For poorly soluble drugs, surfactant (such as polysorbate 80) or cyclodextrin inclusion compound can be added to improve the dissolution of the drug, thus ensuring the bioavailability of the drug.
② Taste and taste correction technology: Because the water-free oral granules are in direct contact with the oral cavity, taste becomes an important factor affecting patients' acceptance. The use of corrective is essential, and commonly used sweeteners include sucrose, aspartame, stevioside, etc. Aromatics such as strawberry essence and mint essence can improve the smell of particles. In addition, drugs with bad smell or taste can be wrapped by microencapsulation technology to further enhance the patient's medication experience.
③ Stability: The stability of drugs during storage is the key to the development and production of water-free oral granules. It is necessary to investigate the compatibility between drugs and excipients, select suitable packaging materials (such as composite film bag packaging), and control storage conditions (temperature, humidity, etc.). For drugs that are easy to be oxidized, antioxidants (such as vitamin C, butylated hydroxyanisole, etc.) can be added; Drugs sensitive to humidity need to be packaged with good moisture-proof performance, and the environmental humidity should be strictly controlled in the production process.
Fourth, the typical case analysis
Optimization of children's medication: Azithromycin anhydrous granules, aiming at the problem of children's dysphagia, developed a corrective system containing aspartame and citric acid, which improved the medication compliance compared with traditional granules. Clinical data show that the medication error rate of the preparation is reduced by 78% and the incidence of adverse reactions is reduced by 43% among children aged 3-7 years. Its core technology lies in: the coating process of pellets: bitter taste barrier is realized by three layers of coating (protective layer, isolation layer and taste masking layer); Compound corrective matrix: the synergistic effect of sorbitol and sodium carboxymethyl cellulose improves the smoothness of particles.
Used for immunomodulation: Lactobacillus particles, which are compounded with inactivated Lactococcus lactis subsp. lactis and monosodium fumarate, can increase IgA secretion by activating plasma cell-like dendritic cells. This product can reduce the incidence of upper respiratory tract infection during the preventive use in flu season, and is especially suitable for collective places such as nursing homes. Its innovations include: the stability of inactivated bacteria: the survival period of bacteria is prolonged by absorbing water through magnesium aluminum silicate; Freeze-drying flash release process: the uniform dispersion of bacteria and excipients was realized, and the bioavailability of the preparation was improved.
Used in first aid scene: Loratadine freeze-dried tablets, Loratadine freeze-dried tablets through -196℃ liquid nitrogen quick freezing and vacuum drying process, to achieve 5 seconds disintegration, 15 minutes to take effect. Compared with traditional tablets, its bioavailability is increased by 1.8 times, and the time from administration to symptom relief is shortened by 40% in the first aid of anaphylactic shock. The core advantages of this technology are: ultra-fast disintegration: the micropore structure formed by freeze-drying accelerates water penetration; High activity retention: dehydration at low temperature avoids the degradation of heat-sensitive components.
Water-free oral granules have reconstructed the drug delivery model through the cross-innovation of material science and preparation engineering. With the aggravation of aging society and the diversification of first aid scenarios, such as elderly patients: reduce the risk of choking in drinking water and improve the compliance of cardiovascular drugs; Patients with mental illness: solve the problem of Tibetan medicine and vomiting medicine, and improve the standard rate of blood concentration of antipsychotic drugs; When working in the field, it can meet the demand of first-aid drugs for military, geological exploration and other water-free scenes. The technology platform will show wider application value and provide patients with more convenient and efficient drug selection.
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