Which Medications Can Be Delivered in Patch Form?

A patch is a sheet-like preparation that can be applied to the skin and the drug can produce systemic or local effects. Modern transdermal absorption preparations are a patch or patch drug that is absorbed through the skin and can be quickly and persistently entered into the body through the controlled release mechanism according to the dose required by the condition.

Chinese name: Patch
the way: Stick on the skin

Nature: Flake preparation
Method: diffusion

Patch introduction

The patch has a backing layer, a drug depot with (or without) a controlled release film, an adhesive layer, and a protective layer to be removed before use. Patches can be used on intact skin surfaces as well as on diseased or incomplete skin surfaces. Among them, a patch for intact skin surface, which can transport drugs through the skin and enter the blood circulation system, is called a transdermal patch.

The transdermal patch works through diffusion, and the drug light diffuses directly from the reservoir into the skin and blood circulation. If there is a controlled release film layer and an adhesive layer, it enters the skin and blood circulation through the two layers. The duration of the transdermal patch is determined by its drug content and release rate.

The covering of a transdermal patch is impermeable to the active ingredient and usually impermeable to water.

The reservoir of the transdermal patch may be of a matrix type or a controlled release film type.

The protective layer plays the role of anti-adhesion and protective agent. Usually it is anti-adhesive paper, plastic or metal material. When removed, it should not cause peeling of the storage and adhesive layer.

Patch III. Advantages of the patch:

The advantage of the patch is that it removes the first-pass clearance effect of the liver, avoids the irritation of the gastrointestinal tract by medicinal chemical and biological effects, reduces or avoids the occurrence of side effects, and because the drug is well targeted, the dosage of the drug is also It is greatly reduced, and it is more convenient for patients.

When applied to dry, clean, intact skin surface, light pressure with hands or fingers, the patch can be firmly adhered to the skin surface, which should not cause damage to the skin or cause the preparation to peel off from the backing layer when removed from the skin surface. The patch also does not irritate or cause allergies to the skin after repeated use.

Patch IV, the matrix of the patch

Patches are commonly used in pressure-sensitive adhesive matrices and are a key material in transdermal absorption systems. It refers to a type of adhesive material that can be pasted under slight pressure and easy to peel at the same time, so as to ensure that the release surface is in close contact with the skin, the drug store and the controlled release effect. The molecular weight and molecular weight distribution, the degree of crystallization and crystallinity, the degree of crosslinking, and the glass transition temperature of polymer materials have important effects on the transdermal absorption of drugs. Generally, various pressure-sensitive adhesives are selected according to the solubility, dispersion coefficient and permeability coefficient of the drug in the pressure-sensitive adhesive matrix.

4.1 Polyisobutylene pressure-sensitive adhesive matrix

Polyisobutylene, as the main component of pressure-sensitive adhesive, is an amorphous linear polymer, which has stable performance, heat and water resistance, and good aging resistance. In addition, this type of pressure-sensitive adhesive has a matrix component that is safe and non-toxic, has large drug package capacity, and releases drugs. Unique performance, controllable viscosity, stable matrix performance, and the advantages of large-scale production. At present, most manufacturers of transdermal preparations prepare this kind of pressure-sensitive adhesives. This pressure-sensitive adhesive can use high- and low-molecular-weight polyisobutylene with different proportions as raw materials. Frequently add some tackifier, plasticizer, filler or stabilizer. Low molecular weight polyisobutylene has the effects of increasing viscosity, improving flexibility and wettability, and high molecular weight polyisobutylene has higher peel strength and cohesive strength. In the study of indomethacin film, Lu Xiaohe et al. Used high- and low-molecular weight polyisobutylene mixed matrices. In this type of patch, most of them use pressure-sensitive adhesive matrices as drug depots, and also for adhesive purposes. .

4.2 Polyacrylate-based pressure-sensitive adhesive matrix

Polyacrylate pressure-sensitive adhesive has good cold resistance, heat resistance, stable properties and no pollution. This type of pressure-sensitive adhesive is widely used in transdermal absorption patches. After structural modification, the solubility of the drug can be greatly improved, and it has the advantages of easy diffusion and the like. By the copolymerization of monomers with different structures, ideal products can be obtained. These monomers have different glass transition temperatures. There are two types of acrylate pressure-sensitive adhesives: solution and emulsion. The solution pressure-sensitive adhesive is generally composed of 30% -50% acrylate copolymer and organic solvent. The reaction mixture contains unsaturated olefin acrylic monomer, and the adhesive layer is colorless and transparent. Emulsion-type pressure-sensitive adhesive is a product obtained by adding various thickening agents and neutralizers after emulsion polymerization of various acrylate monomers using water as a dispersion medium. It is stable to heat and ultraviolet rays, and has no organic solvent pollution, but has poor water and humidity resistance. .

The key components of acrylic copolymers are those with low glass transition temperature (Tg) and soft acrylates (such as 2-ethylhexyl acrylate and butyl acrylate), which are used to improve the adhesion of pressure-sensitive adhesives. ; The other type is vinyl acetate with high Tg and rigidity, whose role is to improve the cohesion of pressure-sensitive adhesives, and functional monomers (providing polarity such as acrylic acid) are used for chemical crosslinking to improve cohesion. Some professional companies can make pressure sensitive adhesives for special skins according to the requirements of formulation designers. Some well-known foreign adhesive companies such as 3M and Cori-um have synthesized polyacrylates. Polyisobutylene, polystyrene, or EVA copolymers are graft copolymers with backbones. In the backbone, hydroxyethyl (HEA) or ethylpyrrolidone is attached to control the drug loading. Isooctyl acrylate graft copolymers The formation of large molecules can enhance the strength of the skeleton.

This kind of pressure-sensitive adhesive has good affinity for polar high-energy surface substrates, but cannot wet well to low-energy surface substrates such as polyethylene and polyester, and can be improved by adding wetting agents such as propylene glycol. Acrylic pressure-sensitive adhesives are widely used in the preparation of patches. For example, Qiu Lin et al. Used ligustrazine patch prepared with polyacrylate pressure-sensitive adhesive as a matrix is widely used in clinical treatment of cardiovascular and cerebrovascular diseases, which improves the clinical effect of ligustrazine.

4.3 Silicone rubber pressure-sensitive adhesive matrix

It is a polymer formed by the condensation of a low molecular weight silicone resin and a linear polydimethylsiloxane fluid. It is both a viscosity-adjusting component and a cohesive strength-adjusting component, but the adhesive force is small. The key to production is the base material. Choice of surface treatment and release paper. In order to increase the drug loading capacity of the silicone rubber pressure-sensitive adhesive matrix, it is sometimes necessary to add a pH adjuster to change the pH value of the matrix or add a polymer compound to increase the solubility of the drug in the matrix. Adding a crosslinking agent can change the flexibility and cohesive strength of the silicone rubber PSA matrix.

4.4 Silicone PSA Matrix

Silicone PSA is the condensation reaction product of the secondary structure of silicone and its tertiary structure resin. Advantages and disadvantages: Silicone pressure-sensitive adhesive is safe for human application, but it is more expensive. This kind of adhesive is softer, harder than adhesive tape, and has a slightly lower peeling effect than rubber adhesive. However, the viscosity loss after repeated use is not significant. This product is not very soluble for most drugs, but has good diffusibility. A variety of silicone pressure-sensitive adhesives have been sold in foreign markets. Commonly used are: silicone pressure-sensitive adhesives suitable for amine-containing drugs (BIO-PSAQ7-2920) and silicone pressure-sensitive adhesives not suitable for amine-containing drugs (DowComing355 medical pressure-sensitive adhesive). According to the needs of the user, the initial viscosity of the solid component can be adjusted with an appropriate solvent.

V. Methods for promoting drug penetration

The biggest barrier for transdermal administration is the skin. Therefore, if the drug penetrates the skin for prevention or treatment, it requires a certain transdermal rate. In general, only a few drugs can work, and the transdermal rate of most drugs can not meet the treatment requirements. Therefore, increasing the transdermal rate of a drug is the key to developing a transdermal drug delivery system.

5.1 Transdermal absorption enhancers

It refers to materials that penetrate into the skin and reduce the resistance of the drug to the skin. Commonly used accelerators are dimethyl sulfoxide, laurone, organic solvents (such as ethanol, propylene glycol), fatty acids and fatty alcohols (such as oleic acid), and surfactants (such as Planic, sodium dodecyl sulfate, Tween-80) and so on. At present, research on penetration enhancers is not limited to chemicals, and is gradually turning to natural products and biosynthetic products. The study also found that papain, Chitosan, etc. also have different penetration promoting effects under different conditions. In recent years, studies have suggested that Azone has a strong penetration promoting effect, low effective concentration, stable properties, low toxicity, and no side effects, and can be widely used in transdermal absorption preparations. It has also been found that traditional Chinese medicine transdermal absorption enhancers have the advantages of good effects and small side effects, and are currently receiving increasing attention. For example, many traditional Chinese medicine transdermal absorption enhancers have been found in terpenes, alkaloids and lactones. It has been reported that the C2-traditional Chinese medicine penetration enhancer prepared with cinnamon extract and another aromatic extract has a faster effect than Azone. If the transdermal absorption enhancer has a coordinated effect, the combined use can reduce the amount of the accelerator used, reduce unnecessary toxic and side effects, and make the amount of the main medicine small and effective.

5.2 Iontophoresis

This method uses direct current (usually> 500mA / cm) to introduce charged or neutral drug particles into the skin through the electrodes, thereby entering the blood circulation. This method is particularly suitable for the transdermal administration of peptides and proteins and those drugs that are difficult to work with a transdermal enhancer. It can solve the problem of transdermal administration of some drugs that are difficult to penetrate the skin under the passive diffusion mechanism, such as water-soluble drugs, ionic drugs, peptides and protein macromolecular drugs, etc. Controllable release and use with biosensors. Manebe et al. Found that iontophoresis can enlarge the pores on the skin barrier or generate new pores, thereby promoting the penetration of non-ionic hydrophilic drugs.

5.3 Electroporation

Electroporation is a process that uses transient high-voltage pulsed electric fields to form temporary, reversible hydrophilic pores in lipid bilayers such as cell membranes to increase the permeability of cells and tissue membranes. This technology can significantly promote the percutaneous penetration of hydrophilic macromolecular drugs. The main drugs currently being developed or applied by electroporation are: luteinizing hormone (LHRH), fentanyl, heparin, calcein, oligomeric Nucleotides, etc., confirmed the feasibility of transdermal administration of macromolecular drugs by electroporation.

5.4 Ultrasound introduction method

Ultrasound introduction is a process in which drug molecules pass through the skin or enter soft tissues through mechanisms such as cavitation, convective transport, mechanical effects, and thermal effects. The factors affecting the introduction of ultrasound are mainly the ultrasound itself, including its frequency, intensity, application time, and procedures. This method is still immature and there are many problems to be solved.

5.5 Laser Technology

A certain intensity laser is irradiated on the surface of the target material, and a high-amplitude pressure wave is generated. Its properties depend on the characteristics of the laser (wavelength, pulse time, light intensity) and the opto-mechanical properties of the target material. It acts on the drug molecules in the drug store, prompting it to penetrate the skin efficiently.

5.6 Microneedle Transdermal Drug Delivery Technology

This is a micro-injection release method that can target specific layers of the skin. It is a novel dual-release method that combines the advantages of a hypodermic syringe and a transdermal patch. It does not cause pain during drug delivery. The main advantage of this release method is that the administration can be adjusted or discontinued at any time, and it is especially effective for adjusting the dose of insulin or analgesics. The microneedle preparations need to further solve the following problems when entering the market: how to ensure that the microneedles with drug layers are not pinched when inserted into the skin, how to ensure that hollow microneedles are not blocked, and how to enhance the repeatability of microneedle array Exploitability etc.

5.7 Acupoint Administration

The acupoint transdermal administration is to make the medicine into a certain dosage form and act on certain acupoints. The stimulating and pharmacological effects of the medicine on acupoints are used to adjust the body and treat diseases. Acupoint transdermal drug delivery is an ancient method of treating diseases based on the theory of traditional Chinese medicine meridian, which has the characteristics of simplicity, convenience, cheapness and experience. God shrines are acupuncture points commonly used in acupoint transdermal administration. The epidermal layer is very thin and there is no fat tissue below the umbilicus. The venous network and nerves around the umbilicus are abundantly distributed, so the penetration is strong and fast. The indications for umbilical therapy are quite extensive, involving pediatrics, internal medicine, gynecology, facial features, and emergency department. Liu Jianping studied the effect of transdermal absorption of aminophylline patches in different acupoints. The test results show that Feishu and Tongzhong points are beneficial to transdermal absorption of aminophylline.

Patch VI. Determination of Adhesion of Patches

In addition to traits, forming tests, in vitro release tests, and skin irritation tests, new products often need to be tested for the stability of the patch, such as peel test and peel force measurement, which is also the market for the government. The content of the application requiring quality inspection.

6.1 Initial viscosity measurement

The classic rolling ball method was used to passively roll the steel ball off the inclined surface and measure it through the rubber surface placed in a horizontal position. There is a negative correlation between the distance rolled out and the adhesion.

6.2 Determination of stickiness

Stick the sticky surface of the patch on the surface of the test board placed vertically, leave a section below, and hang a weight of a certain quality in the vertical direction, and record the time that the patch slides until it falls off and the displacement distance within a certain time. .

6.3 Peel strength determination

Paste the adhesive surface of the patch on the surface of the test board, place it horizontally, peel it at a certain speed along the horizontal or vertical direction, and record the force during the peeling process. According to national standards, it refers to the separation of glued samples under specified conditions. The load that the unit width can bear is expressed in kN / m.

Production and storage of patches

During the production and storage of the patch, the following relevant regulations shall be met.

First, the materials and auxiliary materials used in the patch should meet the relevant national standards, non-toxic, non-irritating, stable in nature, and do not work with drugs. Commonly used materials are aluminum foil polyethylene composite film, release paper, ethylene vinyl acetate copolymer, acrylic or polyisobutylene pressure-sensitive adhesive, silicone rubber, and polyethylene glycol.

2. The patch can be added with surfactants, emulsifiers, humectants, preservatives or antioxidants as needed. A transdermal patch may also include a transdermal enhancer.

3. The appearance of the patch should be complete and smooth, with a uniform application area, and the punching incision should be smooth without sharp edges.

4. The drug can be dissolved in the solvent and filled into the depot. There should be no air bubbles in the depot and no leakage. Drug suspension in the preparation must ensure uniform suspension and coating.

5. The coating of pressure-sensitive adhesive should be uniform, and the residual solvent should be checked when coating with harmful solvents.

Sixth, the use of ethanol and other solvents should be indicated in the package, should be used with caution for allergies.

7. Unless otherwise specified, the patch should be stored under seal.

8. The patch should indicate in the label the dosage of the drug contained in each patch, the total duration of action and the effective area of drug release. Transdermal patches should also indicate the amount of drug released per unit time.

Patch VII, Outlook

In recent years, transdermal preparations have developed rapidly, and research on patches has also made great breakthroughs. With its unique advantages, it is increasingly valued by the pharmaceutical industry. The 2005 edition of the Pharmacopoeia has contained the standard requirements for estradiol sustained-release patches and indomethacin patches, and has developed a method for measuring the adhesive force of patches. At present, we have developed a patch that is simple, practical, effective, and easy to control the production process, and has achieved higher social and economic benefits, and its development prospects are still broad, and the market potential is huge, and it is worth continuing research.

Of course, basic research on transdermal preparations of traditional Chinese medicine can be tried. For example, to find new penetration enhancers from traditional Chinese medicine or natural products, to build new drug delivery platforms for transdermal preparations of traditional Chinese medicine, to use modern fingerprint technology of traditional Chinese medicine to find reasonable methods to study the penetration kinetics of traditional Chinese medicine, and to penetrate the skin in traditional Chinese medicine. Research on enzymatic hydrolysis kinetics and mathematical models in the skin, research on the correlation between transdermal drug delivery experiments in vivo and in vitro, and development of new technologies or methods for transdermal drug delivery applications.

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