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As a pharmaceutical excipient, PVP is mainly used as a binder for tablets and granules, a cosolvent for injections, a stabilizer, a dispersant for liquid preparations, a coating film-forming agent and a pigment dispersant, a coprecipitation agent for insoluble drugs, an extender and a lubricant for ophthalmic drugs. The key points of PVP in pharmaceuticals are introduced as follows:
Pharmaceutical tablets should have a certain mechanical strength so that they will not break and maintain good physical properties when subjected to inevitable collision and friction in the process of production, transportation, sub packaging and sales; At the same time, it has satisfactory performance characteristics when taking, and can quickly disintegrate in the digestive tract and release drugs. The key to solve this problem is to choose the ideal binder. Whether wet granulation, dry granulation or direct tablet pressing process, PVP with strong adhesion, good compatibility with human body and strong solubility can fully meet the above requirements. At present, it has been widely used in various drug tablets.
For drugs with high moisture absorption, PVP can be dry mixed with other powders, and then wetted with appropriate solvent during granulation. The use of PVP helps to prepare compressible particles that can flow freely, and finally produce hard tablets with strong solubility. The dosage of pvpk30 in tablets is generally 2 ~ 5%, and the use concentration is generally 0.5 ~ 5%. Pvpk90 has strong adhesion and small dosage, about 1-3%. The high solubility and adjustable viscosity of PVP reduce the volume of granulation solution, thus reducing the drying time and cost.
Because PVP is soluble in both water and organic solvents such as ethanol, PVP can actually be used in most prescriptions. Especially for those water sensitive, heat sensitive and volatile drugs, such as oral long-acting contraceptives chlormadinonum, Nitroglycerinum and aspirin, if the alcohol solution of PVP is used for granulation, the stability problem is solved, the drying temperature is reduced, the drying time is shortened and the drug quality is guaranteed.
Different PVP varieties and specifications are suitable for different granulation and production processes, and the properties of the newly obtained tablets are also different. Learn about the polyvinylpyrrolidone use in pharmaceuticals.
Wet granulation adhesive makes the prescription "adhesive", so as to improve its compressibility and fluidity. This not only plays an important role in the physical properties of tablets, but also has an important impact on the bioavailability and curative effect of tablets.
Povidone series products are the preferred high-efficiency adhesive for wet granulation.
Direct tablet pressing and dry granulation are becoming more and more popular in tablet production. Dry adhesives are usually composed of fillers or filling adhesives with good compressibility. The latter can not only improve the adhesion of active ingredients, but also form a considerable part of the tablet weight. Most filling adhesives also act as tablet disintegrating agents to a certain extent. If the formula contains a high dose of drugs or to improve the bonding performance of the filling adhesive. In these cases, especially in direct tablet pressing, the adhesive must be ground and have particularly superior powder fluidity to ensure ideal dispersion.
Improving the solubility, dissolution rate and bioavailability of slightly soluble and insoluble drugs is a problem that must be solved in pharmaceutical research and production.
Many drugs have good curative effects, but their bioavailability is reduced due to their low solubility in water. Using some water-soluble carriers to coprecipitate with drugs can improve the dissolution and dissolution rate of drugs, improve the curative effect and reduce the dose. The size of the polymer and the shape of the polymer (macromolecule) are suitable for the formation of the polymer (macromolecule) and the polymer (macromolecule) is the "solid carrier".
The study of drug PVP coprecipitation began in the 1960s. Tachibarla first reported the preparation of B-carotene aqueous dispersion with PVP to improve the dissolution rate of B-carotene. Subsequently, the research reports on the improvement of solubility, dissolution rate and absorption rate of the coprecipitate of griseofulvin, lixueping drugs and PvP are often found in the literature.
Because the carbonyl group in PVP molecule is combined with the active hydrogen atom in insoluble drug molecule by hydrogen bond, the drug molecule becomes amorphous and enters the fully water-soluble PVP macromolecule, which inhibits the formation and growth of crystallization of insoluble drug small molecules and becomes supersaturated, which greatly improves the solubility of insoluble drugs. For example, phenytoin is a slightly soluble drug, which usually can not reach the effective blood concentration (10 ~ 15) μ G / ml), but when the coprecipitate of 1:5 is formed with PVP, its concentration in the dissolution medium with pH = 1.2 is 2.3 times higher than that of phenytoin. The effective blood concentration can be reached within two hours after oral administration, and the maximum blood concentration can be more than twice.
The solubility and dissolution rate of indole alkaloid morpholine in water are very low. The dissolution rate constant at 30 ℃ is 0.023min-1, but the 1:5 PVP coprecipitation not only increases its solubility by 38 times in 10 minutes, but also increases its dissolution rate constant by 130 times to 2.99min-1, and the PVP concentration increases by 0.6 × 10-3m, solubility increased by 1 × 10-3M. This is because the number of molecules bound by hydrogen bond between each PVP molecule and morpholine is certain. With the increase of the relative content of PVP, the proportion of morpholine molecules in the bound state in the total morpholine molecules increases, thus improving the solubility.
The dissolution rate of reserpine is greatly affected by its crystal size. 6~30 μ The dissolution rate of M crystal is 297~420 μ 6 ~ 7 times of M crystal. When PvP and its coprecipitation, the particle size can become smaller. Therefore, the solubility and dissolution rate of reserpine and PvP coprecipitation are higher than that of its mixture with PVP and reserpine itself. Moreover, the greater the proportion of PVP, the greater its solubility and dissolution rate. 1: Co precipitate of 3 and co precipitate of 1:6 (particle size 297 ~ 420) μ m) The dissolution rate was reserpine (particle size 6 ~ 30) μ m) The dissolution half lives are 7 minutes, 0.5 minutes and 106 minutes respectively.
The coprecipitation of PVP and trimethoprim (TMP) can improve the dissolution of TMP. The dissolution test of coprecipitate, pure TMP and the mechanical mixture of PVP and TMP showed that the coprecipitate of PVP and TMP (3 ∶ 1) dissolved the fastest.
Changing the weight ratio of PVP to drug can adjust the drug dissolution rate of coprecipitate, which can also be explained from the following examples. For example, the coprecipitation system of cyclohexylurea acetate and PvP must ensure the amorphous dispersion of cyclohexylurea acetate when the PVP content reaches more than 70%, so as to achieve the purpose of rapid dissolution. Otherwise, the dissolution rate of the drug will be reduced due to the formation and increase of crystalline state. For another example, when the weight ratio of PVP to griseofulvin is reduced from 20:1 to 5:1, its dissolution rate is also gradually reduced. When the weight ratio of PVP to SF decreased from 20 ∶ 1 to 3 ∶ 1, the dissolution rate of SF increased gradually, but when the amount of PVP decreased to 0, the dissolution rate was the lowest.
Changing the degree of polymerization of PVP can also adjust the drug dissolution rate of coprecipitates. Generally speaking, when the degree of polymerization of PVP increases, the drug dissolution rate decreases. For example, St, SMZ and STZ form coprecipitates with pvpkl5, povidone PVP k30 and China povidone k90 respectively, and their dissolution rate V follows the following law vk15 > vk30 > vk90. Other coprecipitates formed with PVP such as Dihydrochlorothiazide, sulfathiazole, chloramphenicol, furosemide, digoxin, chlorothiazide, hydrocortisone and prednisone also follow this law, with the exception of nifedipine and phenytoin.
The increase of solubility and dissolution rate of insoluble drugs will inevitably lead to the increase of gastrointestinal absorption rate and drug concentration in blood, and the bioavailability of drugs will increase. For example, human trials showed that the bioavailability of phenytoin PVP coprecipitate increased by 1.54 times, while it increased by 2.37 times in the first LO hours after administration. The bioavailability of digitonin PVP was increased by 18.5 times.
In the coprecipitates described in the previous section, the solubilization of PVP mainly plays a role in tablets.
Low molecular weight PVP (k value is 12, 15, 17) can also act as cosolvent dispersant or crystal growth inhibitor in injection. This solubilization is mainly caused by the association between drug and PVP.
PVP is also used as cosolvent or stabilizer in injection or liquid preparations: oxytetracycline, testosterone, doxycycline, progesterone, sulfathiazole, diethylstilbestrol, allopurinol, furanone, defatted soybean lecithin, diphenylhydrin, cyclohexane sulfamate, etc.
In the powder injection, PVP was added to Merck, Xiapu, rifampicin of Dow Chemical Company and doxycycline of Pfizer company. In China, 2% PVP was used as the solubilizer of bishuping injection; Adding PVP to chloramphenicol suspension for injection can make the particle fineness < 5 μ m.
There are many examples of PVP K25 and K30 solubilizing in oral or external liquid preparations. For example, PVP can improve the stability of protease and prevent sugar from crystallization from liquid; The precipitation of some two immiscible components from aqueous solution can also be overcome by adding PVP. A typical formula is paracetamol syrup, which uses pvpk25 to increase the solubility of the drug and reduce its bitterness.
Pvpk25, K30 and K90 can also be used as stabilizers for oral and external drug dispersions, for example, (acycovir); Ibuprofen; (magalarate)； Nystatin; Phenytoin; Trimethoprim; Sulfonamides; There are antibiotics, sugar coating dispersion, etc. The combination of pvpk90 and PVPP often has a very good stability effect.
The addition of pvpk25 and K30 in the drug film coating can not only increase the adhesion of the coating to the drug base material due to the high adhesion of PVP, but also increase the stability of the coating suspension due to its excellent dispersion and avoid the re aggregation and migration of pigments. The excellent film-forming property of PVP can also prevent micro cracks on the coating surface during drying. However, it should be noted that due to the easy hygroscopicity and stickiness in the air, soluble PVP can not be used as a single film-forming agent, but should be combined with cellulose derivatives, methacrylic acid, tree esters and other film-forming agents. The pigment dispersion containing alcohol can be prepared with shellac and PVP, especially in spray and fluidized-bed coating equipment, which can obtain uniform coating and improve the dissolution rate of film-forming agent in water.
Controlled release of drugs is a new technology to prolong the action time and control the action intensity of drugs. Because PVP has molecular association with many drugs, controlling the association degree of PVP and drugs can prolong the release and absorption of drugs in vivo, so as to prolong the effect and slow release. This effect can be adjusted by selecting appropriate molecular weight and concentration. For example, low concentration of PVP will prolong the dissolution of hydrofluorothiazidium, while high concentration of PVP will greatly increase its dissolution rate. PVP can not only increase the solubility of paracetamol, but also delay its dissolution rate. This is because the dissolution of paracetamol decreases with the increase of solution viscosity, and the molecular weight and concentration of PVP will affect the viscosity of the solution. 1:9 paracetamol dispersions were prepared by pvpkl7, K30 and K90 respectively. The results showed that the dissolution rate of pvpkl7 was similar to that of pvpk30, while that of pvpk90 was the slowest.
The effect of PVP on the dissolution rate of cholesterol and hormone drugs is also related to the content of PVP. PVP can reduce the solubility of the former and increase the solubility of the latter, such as testosterone, progesterone and diethylamine diethylstilbestrol. The decrease or increase value is directly proportional to the concentration of PVP.
It is reported that 10 ~ 25% PVP solution can prolong the effects of penicillin, chloramphenicol, insulin, sodium salicylate, sulfathiazole, phenobarbital, procaine, cortisonum, p-aminobenzoic acid and paracetamol.
Adding a certain amount of PVP into eye drops can increase the solubility of drugs, reduce the irritation of drugs to eyes, increase film-forming, improve viscosity and prolong the action time of eye drops in eyes; Because PVP is hydrophilic and has lubricating effect, it can also be used as artificial tears, especially for those wearing contact lenses.
Extrapharmacopeia version 28 collects two prescriptions of PVP eye drops, which are valid for two years. At present, the disinfectants and lubricants for imported contact lenses sold on the market generally also contain PVP. In the trial production of long-acting eye mask in China, PVP is added into the controlled-release layer as a porogen, which is well compatible with EVA, and the obtained eye mask is smoother and softer.
In the process of filling drugs with capsule filling machine, in case of light powder and small specific volume, 1 ~ 2% PVP ethanol solution can be added to help granulation and improve the flow capacity. In foreign countries, PVP is used as a flow aid in hard capsules, such as cyclic mandelic ester, propylamine, hydroxyethyl pyruvate, ethyl papaverine long-acting capsules, etc. There are few reports on the application of PVP in soft rubber pills. Japanese chemical pharmaceutical company added a small amount of PVP (2%) as dispersant when preparing nifedipine soft pills.
Highly crosslinked PVP, i.e. crosslinked povidone, is an insoluble polyvinylpolypyrrolidone PVPP, which can be used as disintegrating agent for tablets or hard capsules. Wet tablet pressing or direct tablet pressing can be adopted. The tablets or hard capsules prepared by using ppvp as disintegrating agent dissolve in water, and the rapid water absorption and expansion cause high stress in the agent, resulting in the rapid disintegration of the agent.
