Application of povidone PVP in pharmaceutical excipients

As a pharmaceutical excipient, PVP is mainly used as a binder for tablets and granules, a co-solvent for injections, a stabilizer, a dispersing agent for liquid preparations, a coating film forming agent and a pigment dispersing agent, a co-precipitating agent for insoluble drugs, a delayed action agent for ophthalmology, and a lubricant. The main points are described as follows:

l, binder:

The drug tablet should have a certain mechanical strength so that it will not be broken and maintain good physical properties when it is subjected to the inevitable impact and friction in the process of production, transportation, packaging and sales; At the same time, when taken, it has satisfactory performance characteristics and can quickly disintegrate in the digestive tract and release the drug. The key to solve this problem is to choose the ideal binder. Whether it is wet granule, dry granule or direct tablet process preparation of strong bonding ability, good compatibility with the human body, strong dissolution ability of PVP fully meet the above requirements, has been widely used for various drug tablets.

For drugs with high hygroscopicity, PVP can be dry mixed with other powders, and then moistened with appropriate solvents during granulation. The use of PVP helps to produce compressible particles that can flow freely, resulting in hard tablets with strong solubility. The dosage of PVPK30 in tablets is generally 2 ~ 5%, and the use concentration is generally O.5 ~ 5%. The bonding capacity of PVPK90 is strong and the dosage is small, about 1-3%. The high solubility and adjustable viscosity of PVP reduces the volume of the granulation solution, thereby reducing 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 water-sensitive, heat-sensitive and volatile drugs, such as Chlormadinonum, Nitroglycerinum, Achidum Acetylsalicylicum, etc., if PVP alcohol solution is used to form granules, It not only solves the stability problem, but also reduces the drying temperature, shortens the drying time, and ensures the quality of the drug.

(1) wet material binder

Different PVP varieties and specifications are suitable for different granulation and film-making processes, and the properties of newly obtained tablets are also different.

The wet pellet adhesive makes the prescription “adhesive”, thereby improving its compressibility and fluidity. This not only plays an important role in the physical properties of the tablets, but also has a significant impact on the bioavailability and efficacy of the tablets.

Povidone series products are the preferred efficient adhesive for wet granulation.

(2) Direct tablet and dry material adhesive

Direct pressing and dry granulation are becoming more and more common in tablet production. Dry adhesives usually consist of a better compressible filler or a filler, which both improves the bonding ability of the active ingredient and constitutes a considerable part of the tablet weight, and most of the filler adhesives also act as a tablet disintegrator to some extent. If the formulation contains high doses of drugs or to improve the bonding properties of the filling adhesive. In these cases, especially when pressing directly, the adhesive must be finely ground and have a particularly superior powder flow to ensure an ideal dispersion.

2. Coprecipitant

To improve the solubility, dissolution rate and bioavailability of slightly soluble and insoluble drugs is a problem that must be solved in pharmaceutical research and production.

There are many drugs with good efficacy, but their bioavailability is reduced due to their small solubility in water. Using some water-soluble carriers to co-precipitate drugs can improve the dissolution degree and dissolution speed of drugs, improve the therapeutic effect and reduce the dose. This co-precipitate is a polymer (carrier) to the inclusion of small molecules (guest), is a certain shape, size of the appropriate small molecule drug filled in a certain shape, size and structure of large molecules (mostly polymer) space and formed by the “solid solution”.

The research of drug-PVP co-precipitates began in the 1960s. Tachibarla first reported that PVP was used to prepare water dispersions of B carotene to improve the dissolution rate of B carotene. Subsequent studies on the solubility, dissolution rate and absorption rate of coprecipitates of griseofulvin, Lixue and PVP have been frequently reported in the literature.

Since the carbonyl in PVP molecules and the active hydrogen atoms in the insoluble drug molecules are combined by hydrogen bonds, the drug molecules become amorphous and enter the completely water-soluble PVP macromolecules, thus inhibiting the formation and growth of crystals of small molecules of insoluble drugs and becoming susaturated, which greatly improves the solubility of insoluble drugs. For example, phenytoin is a slightly soluble drug that usually does not reach an effective blood concentration (10-15 μg/ml), but when formed with PVP: After the co-precipitate of 5, the concentration of phenytoin in the dissolved medium at PH=1.2 is 2.3 times higher than that of phenytoin, and the effective blood concentration can be reached in less than two hours after oral administration, and the maximum blood concentration that can be achieved is more than twice increased.

The solubility and dissolution rate of the indole alkaloid morpholine in water are very low, and the dissolution rate constant at 30℃ is 0.023min-1, but 1: The PVP coprecipitate of 5 not only increased its solubility 38 times within 10 minutes, but also increased its dissolution rate constant 130 times, reaching 2.99min-1, and the PVP concentration increased by 0.6× 10-3m, and the solubility increased by 1× 10-3m. This is because the number of molecules for each PVP molecule to hydrogen bond with morpholine is certain, and the proportion of morpholine molecules in the combined state increases with the increase of the relative content of PVP, thus improving the solubility.

The dissolution rate of reserpine is greatly affected by its crystal size. The dissolution rate of crystals from 6 to 30μm is

6-7 times that of 297 ~ 420μm crystals. When PVP is co-precipitated with PVP, its particle size can become smaller, so the solubility and dissolution rate of reserpine and PVP co-precipitate are higher than the mixture with PVP and reserpine itself. And the larger the proportion of PVP, the greater the solubility and dissolution speed. The dissolution rates of 1:3 coprecipitate and l: 6 coprecipitate (particle size 297 ~ 420μm) were 15 and 200 times higher than that of serpine (particle size 6 ~ 30μm), and the dissolution half-lives were 7, 0.5 and 106 min, respectively.

The co-precipitation of PVP with trimethoprim (TMP) can improve the dissolution of TMP. The dissolution tests of co-precipitate, pure TMP, PVP and mechanical mixture of TMP showed that the co-precipitate of PVP and TMP (3:1) dissolved the fastest.

The rate of drug dissolution of the coprecipitate can be regulated by changing the weight ratio of PVP to drug, as also illustrated by the following example. For example, the coprecipitation system of cyclohexylurea acetate and PVP must ensure the amorphous dispersion of cyclohexylurea acetate when the content of PVP reaches more than 70%, so as to achieve the purpose of rapid dissolution, otherwise the drug will decrease the dissolution rate due to the formation and increase of crystallization state. For example, when the weight ratio of PVP to griseofulvin is reduced from 20:1 to 5:1, its dissolution rate also gradually decreases. When the weight ratio of PVP to SF is reduced from 20:1 to 3:1, the dissolution rate of SF is gradually increased, but when the amount of PVP is reduced to 0, the dissolution rate is lowest.

Changing the polymerization degree of PVP can also adjust the drug dissolution rate of the coprecipitate. Generally speaking, when the polymerization degree of PVP increases, the drug dissolution rate decreases. For example, ST, SMZ and STZ form co-precipitant with PVPKl5, PVPK30 and PVPK90 respectively, and their dissolution rate V follows the following rule: VK15>VK30>Vk90, Other coprecipitates formed with PVP, such as dihydrochlorothiazide, sulfathiazole, chloramphenicol, furosemide, digoxin, chlorothiazide, hydrocortisone, prednisone, etc., also conform to this rule, while nitrophenyridine and phenytoin are exceptions.

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 also increase. For example, human trials demonstrated that the bioavailability of phenytoin-pvp coprecipitate increased by 1.54 times and by 2.37 times in the first lO hours after administration. The bioavailability of PvP was increased by 18.5 times.

3, co-solvent or dispersion stabilizer

In the coprecipitates mentioned in the previous section, the solubilization effect of PVP mainly plays a role in tablets.

Low molecular weight PVP(K value 12,15,17) can also act as a co-solvent dispersant or a crystal growth inhibitor in injection, and this solubilization effect is mainly caused by the association of drugs and PVP.

In injection or liquid preparations, PVP as a co-solvent or stabilizer are also: oxytetracycline, testosterone, doxycycline, progesterone, sulfathiazole, ethylstilbestrol, allopurinol, furanotazone, defatted soy lecithin, diphenylhexin, cyclohexane aminosulfonate, etc.

In the powder injection, the United States Merck, Xia Pu, Dow Chemical company’s rifampicin, Pfizer’s doxycycline are added to PVP. In China, 2% PVP was used as solvent enhasing for Bizouping injection. When PVP was added to chloramphenicol suspension for injection, the fineness of the particles was less than 5μm.

In oral or topical liquid preparations, there are also many examples of solubilizing effects of PVPK25 and K30. For example, PVP can improve the stability of protease and prevent the crystallization of sugar from liquid; Some insoluble components precipitate from aqueous solutions and can also be overcome by adding PVP. One of the typical formulations is paracetamol syrup, which increases the solubility of the drug with PVPK25 and lessens its bitter taste.

PVPK25,K30, and K90 can also be used as stabilizers in oral and topical drug dispersions, e.g., acycovir; ibuprofen; (magalarate); nystatin; phenytoin; trimethoprim; sulfonamides; There are antibiotics, icing dispersion and so on. The combination of PVPK90 and PVPP often has a very good stabilizing effect.

4. Coating or film forming agent

The addition of PVPK25 and K30 to the drug film coating can not only increase the adhesion of the coating to the drug base due to the high adhesion of PVP, but also increase the stability of the coating suspension due to its excellent dispersion, and avoid the reunion and migration of pigments. The excellent film formation of PVP also prevents fine cracks on the coating surface during drying. However, it should be noted that soluble PVP cannot be used as a single film forming agent due to its easy hygroscopic property and stickiness in air, but should be combined with cellulose derivatives, methacrylic acid, resin and other film forming agents. The pigment dispersions containing alcohol can be prepared by shellac and PVP, especially in spray and fluidized bed coating equipment, uniform coating can be obtained, and the dissolution rate of film forming agent in water can be improved.

5, delay agent, sustained release agent

Controlled release of drugs is a new technique to prolong the action time and control the action intensity of drugs. Because PVP has molecular association with many drugs, controlling the degree of association between PVP and drugs can prolong the release and absorption of drugs in the body, so as to play a delayed effect and slow release. This effect can be adjusted by selecting the appropriate molecular weight and concentration. For example, low concentrations of PVP will prolong the dissolution of Hydroflumethiaziclum, while high concentrations of PVP greatly increase the dissolution rate. PVP can not only increase the solubility of Paracetamolum, but also delay its dissolution rate. This is because the dissolution of paracetamol decreases as the viscosity of the solution increases, and the molecular weight and concentration of PVP both affect the viscosity of the solution. PVPKl7, K30 and K90 were used to prepare 1:9 paracetamol dispersions respectively. The results showed that the dissolution rate of PVPKl7 and PVPK30 was similar, while the dissolution rate of PVPK90 was the slowest.

The influence 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, diethylamine-ethylstilbestrol, etc. The decrease or increase value is proportional to the concentration of PVP.

It is reported that The effects of 10-25% PVP solution on penicillin (Berlzyperlici¨num), Chloramphenicdum, insulin (Insulinum), sodium salicylate, Sulfathiazole, Phenobarbitalum, and Propyl Procainum, Cortisonum, paraminobenzoic acid, Paracetamolum all have a delayed effect.

6. Eye medicine additives

Adding a certain amount of PVP in the eye drops can increase the solubility of the drug, reduce the irritation of the drug on the eye, increase the film formation and improve the viscosity, and prolong the action time of the eye drops. Because PVP is hydrophilic and has lubricating effect, it can be used as artificial tears, (the addition amount is (2 ~ 10%), especially suitable for wearing contact lenses.

Extrapharmacopeia Edition 28 collects two PVP eye drop prescriptions, valid for two years. At present, imported contact lenses sold on the market with disinfectants, lubricants, etc., generally contain PVP. In the domestic trial production of long-acting eye film, PVP is added in the controlled release layer as a pore-causing agent, which can be well compatible with EVA, and the resulting eye film is more smooth and soft.

7, capsule flow aid

In the process of filling drugs with capsule filling machine, if light powder is encountered and the specific volume is small, l ~ 2%PVP ethanol solution can be added to help granulating and improve flow capacity. PVP was used abroad as a flow aid in hard capsules including cyclomandelate, propylpyramine, hydroxyethyl pyramic acid and ethyl paparine long-acting capsules. The application of PVP in soft pellets was rarely reported. A small amount of PVP(2%) was added as a dispersant in the preparation of nitrophenidine soft pellets by Japanese Chemical pharmaceutical Company.

8. Disintegrating agent

Highly cross-linked PVP, known as crosslinked POvidone, is an insoluble PVP(PVPP) that can be used as a disintegrating agent for tablets or hard capsules, and can be wet pressed or directly pressed. When the tablets or hard capsules made of PPVP are dissolved in water, the rapid water absorption and expansibility cause high stress in the agent and make the agent disintegrate rapidly.