Topical patch definition

This benefit especially refers to topical routes, as this usually offers avoidance of potentially serious adverse effects when analgesics are administered by systemic routes.

For example, opioids administered by a transdermal route are absorbed into vessels located in subcutaneous tissue and, subsequently, are conveyed in the blood to opioid receptors localized in the central nervous system CNS Figure 1 [ 2 ].

Non—steroidal anti—inflammatory drugs NSAIDs applied topically are absorbed into systemic circulation in a limited percentage, and the main mechanism of action is based on a high concentration in the structures of joints and the provision of local anti—inflammatory effects. Lidocaine and capsaicin in patches, capsaicin in cream, EMLA cream, and creams containing antidepressants e.

Transdermal and topical routes of opioid administration are also associated with a lower risk of addiction compared to oral and parenteral routes of opioid analgesics administration. Benefits associated with the administration of opioid analgesics through a transdermal route are as follows:.

The use of the transdermal route allows for the avoidance of problems associated with a disturbed absorption of a drug from the gastrointestinal GI tract or other GI problems i. Low concentrations of drugs and small fluctuations of their concentration in the blood serum guarantee long—lasting analgesia with a lower number of adverse effects, especially nausea, vomiting, and constipation.

Features that should be fulfilled by a transdermal opioid are as follows: small molecular weight, high lipophilicity, high efficacy to compensate for limited absorption, low melting temperature, relatively short half—life, low daily dose, system dosing providing absorption from a relatively small area, and matrix patches in which a total amount of a drug is localized homogenously in an adhesion layer.

The above technology ensures regulation of the release of an opioid based on a gradient concentration between a patch and the skin.

The damage of a patch does not evoke an uncontrolled release of an active substance and enables the division of a patch into smaller parts in order to administer a lower dose of a drug, which is especially relevant in older patients.

Natural features listed above ease the crossing of a drug through the skin and are possessed by two opioid analgesics: fentanyl and buprenorphine Table 1. The first drug used in the treatment of pain through the transdermal route was fentanyl. Patches of fentanyl release In patients with fever and in those with excessive sweat, the absorption of the drug may be disturbed due to a layer of sweat separating the active surface of a patch from the skin.

Patients with a patch may take a bath, shower, and swim, although they should not use solariums and saunas. After the fentanyl patch is first applied, the beginning of its analgesic action is delayed by up to approximately 12 h.

Therefore, for this period of time, patients should be treated with other analgesics. In most patients, the fentanyl analgesic effects persist for 72 h 3 days and, for this period of time, a patch should be administered.

In some patients, a decrease of the analgesic effect is observed on the third day. In these patients, a change of patch every 48 h 2 days may be considered. Fentanyl and its metabolite are excreted by the kidneys. The advantages of fentanyl are as follows: compared to morphine, it is less constipating, emetogenic, sedative, and does not release histamine; it is relatively safe in patients with renal failure. Fentanyl in patches is not recommended for the treatment of acute postoperative pain due to a slow onset of analgesic action after the first patch application.

However, in postoperative analgesia, it is possible to use fentanyl administered by a transdermal route through a special micropump system IONSYS , in which the acceleration of opioid absorption is achieved through an iontophoresis process. In this system, a small micro—pump with a diameter of an index finger is attached to the arm skin. For safety reasons, the device possesses a programmed 10—minute refraction period when administration of the drug is impossible.

The number of possible doses administered per day 24 h is In patients treated with fentanyl pumps, a constant monitoring of the respiratory system function is required. Fentanyl products administered by transmucosal routes i. Buprenorphine is available in patches releasing 35, In older patients, a starting dose may equal 8.

A change in the dose should take place after at least two consecutive applications of a patch. The pharmacokinetic steady—state and an equilibrium drug distribution between blood and cerebrospinal fluid are reached after at least five plasma half—lives. Rules of patch applications are the same as that for fentanyl. To decrease the risk of dermatitis induced by a buprenorphine patch, some clinicians recommend keeping the patch in the air to evaporate gaseous substances contained in a patch before putting the patch on the skin; this is recommended only for an original buprenorphine product.

Original buprenorphine patches are normally changed every 3. Dosing twice a week is more convenient for many patients because of fixed days for patch changes. A generic product is normally changed every three days. Buprenorphine has been used in clinical practice for over 30 years, but the interest in the drug increased after introducing transdermal products. Buprenorphine is a semi—synthetic derivative of thebaine.

The buprenorphine molecule contains a basic skeleton of morphine, but there are significant differences between their structures.

It may be predicted that buprenorphine displays some unique and distinguished pharmacological and clinical features while preserving general morphine properties. Buprenorphine strongly binds to opioid receptors, displaying the highest affinity compared to other commonly used opioids. Buprenorphine binds to opioid receptors more slowly and dissociates more slowly than fentanyl, which is associated with less risk of developing opioid withdrawal.

This leaves a significant percentage of opioid receptors free, making it possible to use buprenorphine concurrently with other opioids. However, concurrent treatment with other opioids renders only additive effects. This means that, in this dose range, the drug acts as a pure opioid agonist. A ceiling effect of analgesia is achieved when daily doses exceed 16 mg, which are not used in the clinical practice of pain management. A potentially important, although not fully recognized, role of buprenorphine is the interaction with orphanin receptors, ORL—1.

This receptor is similar to opioid receptors and binds nociceptin, which, after the activation of these receptors, antagonizes the analgesic effects of opioids. This may affect its pharmacokinetics and action, especially in patients with cachexia. In the liver, the drug is metabolized through the cytochrome P— enzyme CYP3A4 to become an active metabolite, norbuprenorphine.

A third of the dose administered by a transdermal route is excreted via the kidneys and two—thirds of the drug is excreted with the stool. Transdermal buprenorphine is recommended for cancer and non—cancer patients with moderate to severe pain intensity of musculoskeletal, neuropathic, and visceral pain.

Apart from pain management, buprenorphine is used in substitution therapy for patients diagnosed with drug addiction. For this indication, its effectiveness is comparable with methadone. Drug concentrations in the blood serum that can render analgesia are achieved within 12—24 h after a first patch application, which accounts for the fact that buprenorphine is similar to transdermal fentanyl and should not be used in the treatment of patients with acute and breakthrough episodic pain.

Transdermal buprenorphine renders a stable concentration of the drug in the blood serum, similar to transdermal fentanyl. It was demonstrated that the profile of adverse effects of transdermal buprenorphine is similar to other opioids. Long—term treatment with the drug is characterized by a low frequency of constipation and CNS adverse effects, such as nausea, vertigo, and weakness.

The low frequency of adverse effects on the CNS might be due to the antagonist action of buprenorphine on the kappa opioid receptor KOR. The low frequency of adverse effects in the GI tract is probably associated with a high lipophilicity of the drug. The safety profile of buprenorphine is better compared to other opioids. Buprenorphine displays less neurotoxic effects compared to other opioids such as fentanyl , especially in older patients and those with dementia.

Clinical studies have demonstrated that buprenorphine dose increments allowed the achievement of good analgesia with a limited risk of respiratory depression. There is evidence from animal studies that most opioids apart from buprenorphine and oxycodone induce some degree of suppression of the immune system through modification of NK natural killer cells function, lymphocytes T, action of interleukin—2, or interferon gamma.

Lack of negative impact on the immune system may improve safety of the drug regarding infections and cancer dissemination. Moreover, a significant advantage of buprenorphine, which is similar to fentanyl, is high safety in using the drug in patients with renal failure [ 4 ].

Tolerance development for analgesia during treatment with transdermal buprenorphine was explored in comparative studies with transdermal fentanyl. Because of the strong analgesic potency of transdermal buprenorphine and the low frequency of tolerance development for analgesia, high doses of the drug in clinical practice are rarely required. Opioids induce analgesia by binding to opioid receptors in the CNS spinal cord and brain.

Opioid receptors have also been shown to be present on peripheral sensory nerve terminals in inflamed tissues. Clinical studies have demonstrated analgesic efficacy when opioids are applied topically in certain situations such as skin ulcers and oral mucositis.

The advantage of administering an opioid topically is the avoidance of systemic adverse effects such as nausea, constipation, and sedation. Morphine may also be administered through the mucosa. Before an application of these morphine formulations on the skin surface, a surgical elaboration of a wound should be conducted because topical opioids may hamper wound closure due to the inhibition of peripheral neuropeptide release into the healing wound.

The duration of action of topical morphine has been reported to be as long as 7—12 h, which is longer compared to morphine administered by oral or parenteral routes 4—6 h. There are ongoing studies on the use of morphine administered systemically in transdermal patches [ 6 ].

All joint structures, apart from cartilage, are very rich in nerves. Thus, pain in joints and bones are usually of severe intensity. Prostaglandins play a main role in the process of inducing peripheral inflammatory pain; therefore, NSAIDs, which have a basic mechanism of action of blocking prostaglandin formation, are an important component in the treatment of this type of pain. The concentration of an NSAID in the blood serum determines its analgesic effects, and its concentration in a joint decides its anti—inflammatory effect.

NSAIDs administered systemically achieve a high concentration in the blood serum and may induce adverse effects in the circulatory system, GI tract, kidneys, and liver [ 7 ]. In contrast to systemic administration, a local application of NSAIDs supports analgesic and anti—inflammatory effects with little risk of aforementioned, potentially serious adverse effects.

Penetration of drugs may be significantly improved through the use of ultrasound and iontophoresis. Concentration of NSAIDs after topical administration in the joint cartilage and in the meniscus is 4—7 times higher compared to that after an oral administration of NSAID; in tendinous cots and in the bursa, it is a few dozen times higher compared to that after an oral administration of NSAID.

In chronic pain with an accompanying inflammatory process, combining a local and orally administered NSAID seems to be a good approach Table 4. Non—steroidal anti-inflammatory drugs used for topical application and their usual concentrations.

EMLA cream is an oil—water lotion containing lidocaine and prilocaine in a ratio. It is a unique local anesthetic formulation, which, thanks to its large water content, is easily absorbed through the skin. In addition, due to the fact that the active substance is present in the form of more active alkaline compounds contained in small lipid drops suspended in water and not in a ionized salt form, it is possible to obtain an effective skin anesthesia up to approximately 0.

This product is a eutectic mixture, which means that the composition of the drug is matched in a way that the melting point of the mixture of both components is different than the melting points of the individual components. In the temperature of human skin, this product preserves a liquid form, thanks to which it has a chance of being absorbed through the skin and inducing its anesthesia. According to the literature, this product may be applied on quite a large skin surface, even over cm 2 , in a single dose of 30—50 g.

A gram of cream contains 25 mg lidocaine and 25 mg prilocaine. Indications for EMLA cream administration include the following: skin anesthesia alleviating acute pain in surgery, limited to small depth of the skin i. When using EMLA cream on a large surface, it is necessary to monitor circulatory system function, lidocaine, prilocaine, and methemoglobin concentrations. VGSC gather in places of nerve injury, initiating repetitive ectopic excitations.

These channels mark a high ability of lidocaine binding and a slow dissociation. Lidocaine released from a patch penetrates through the skin and, to a negligible degree, is absorbed into vessels; therefore, it does not induce circulatory complications and there is no need to monitor circulatory system function.

Lidocaine contained in a patch binds with internal wall VGSC, which are formed in nerve endings and keratinocytes. As a result of blocking VGSC, ectopic excitations are inhibited, but there is no blocking of afferent nerve conduction i.

The second mechanism of lidocaine is associated with an inhibition of the release of nociception process mediators by keratinocytes. Keratinocytes participate in a system of signal transfer, and their activation induces sensitization and depolarization of primary sensory nerve endings through purinergic receptors P2X and an increase in expression of neurokinin receptor NK1 activated by substance P release, which leads to the activation of primary nociceptive sensory nerve endings.

Lidocaine in patches additionally induces an effect of skin cooling hydrogel bandage and provides mechanical protection of skin areas involved in the disease process. The stratum corneum layer the horny layer consists of micrometers of high density, low hydration cell layers. Although this layer is only cells deep, it is the primary barrier. These pathways are not mutually exclusive, with most compounds permeating the skin through a combination of pathways based on the physiochemical properties of the permeating molecule.

While the intercellular lipid bilayers occupy only a small area of the stratum corneum, they provide the only continuous path through the stratum corneum. The permeation process involves a series of processes starting with the release of the permeant the drug from the dosage form vehicle , followed by the diffusion into and through the stratum corneum, then partitioning into the more aqueous epidermal environment and diffusion into deeper tissues or uptake by the cutaneous circulation.

These processes are highly dependent on the solubility and diffusivity of the permeant within each environment. Due to this wide variability in permeability of various drug molecules, several strategies have been developed to facilitate drug permeation through the epidermis.

CPEs are pharmacologically inactive compounds that diffuse and partition the skin and reversibly interact with the stratum corneum components, specifically the intercellular lipid bilayers. The effect is the development of pore or channels in the lipid bilayers through which the drug molecules can pass.

To date, most transdermal delivery systems for pharmaceuticals have been patches. Patches, by themselves, do not enhance the ability of drug molecules to permeate the skin but can increase drug absorption due to prolonged application times. The formulation matrix of the patch, or reservoir, maintains the drug concentration gradient within the device after application so that drug delivery to the interface between the patch and the skin is sustained.

The high drug concentration and occlusive nature of the patch can drive modest amounts of drug through the skin over time, though most of the drug applied remains in the patch.

On-going advances in the development of CPE compounds and technology, such as nanoparticle delivery systems, including micelles, are opening the transdermal route of administration to new and old drugs alike. Micelles are lipid molecules that arrange themselves in a spherical form in aqueous solutions. The formation of a micelle is a response to the amphipathic nature of fatty acids, meaning that they contain both hydrophilic regions polar head groups as well as hydrophobic regions the long hydrophobic chain.

They face to the water because they are polar. The hydrophobic tails are inside and away from the water since they are nonpolar. Micelles can sequester lipophilic drug molecules within the sphere and allow for the movement of these molecules through polar environments.

The transdermal system created by Gensco Pharma utilizes a micelle forming vehicle that encapsulates the drug and combines with CPEs to further increase the amount and rate of permeation.

The increased flux allows for a greater amount of the permeant to move across the skin barrier faster and be available to the deeper tissues and cutaneous circulation than typical patch systems. Medications that are effective for specific conditions but were limited in use due to adverse gastrointestinal effects, high first pass metabolism, and poor bioavailability are now being evaluated for transdermal administration.

Controlled and sustained drug delivery through nanoparticle design and by use of the skin as a drug reservoir is revolutionizing the way we look at transdermal drug administration. We can now truly say we have skin in the drug game.

The firm should have demonstrated the adequacy of the process for dealing with residual material. Heat may also be generated by the action of high energy mixers. It is important to control the temperature within specified parameters, not only to facilitate those operations, but also to assure that product stability is not adversely affected. Furthermore, excessive temperatures may cause insoluble ingredients to dissolve, reprecipitate, or change particle size or crystalline form.

Temperature control is also important where microbial quality of the product is a concern. The processing of topicals at higher temperatures can destroy some of the objectionable microorganisms that may be present. However, elevated temperatures may also promote incubation of microorganisms.

Temperature uniformity within a mixer should be controlled. In addressing temperature uniformity, firms should consider the complex interaction among vat size, mixer speed, blade design, viscosity of the contents and the rate of heat transfer. It is CGMP for a manufacturer to establish and follow written SOPs to clean production equipment in a manner that precludes contamination of current and future batches.

This is especially critical where contamination may present direct safety concerns, as with a potent drug, such as a steroid e. The insolubility of some excipients and active substances used in the manufacture of topicals makes some equipment, such as mixing vessels, pipes and plastic hoses, difficult to clean.

Often, piping and transfer lines are inaccessible to direct physical cleaning. Some firms address this problem by dedicating lines and hoses to specific products or product classes. It is therefore important that the following considerations be adequately addressed in a firm's cleaning validation protocol and in the procedures that are established for production batches. Cleaning procedures should be detailed and provide specific understandable instructions.

For some of the more complex systems, such as clean-in-place CIP systems, it is usually necessary to provide a level of detail that includes drawings, and provision to label valves. The time that may elapse from completion of a manufacturing operation to initiation of equipment cleaning should also be stated where excessive delay may affect the adequacy of the established cleaning procedure.

For example, residual product may dry and become more difficult to clean. As part of the validation of the cleaning method, the cleaned surface is sampled for the presence of residues. Sampling should be by an appropriate method, selected based on factors such as equipment and solubility of residues. Both methods are useful when there is a direct measurement of the residual substance. However, it is unacceptable to test rinse solutions such as purified water for conformance to the purity specifications for those solutions, instead of testing directly for the presence of possible residues.

Because of improved technology, analytical methods are becoming much more sensitive and capable of determining very low levels of residues. Thus, it is important that a firm establish appropriate limits on levels of post-equipment cleaning residues. Such limits must be safe, practical, achievable, verifiable and must ensure that residues remaining in the equipment will not cause the quality of subsequent batches to be altered beyond established product specifications.

During inspections, the rationale for residue limits should be reviewed. Because surface residues will not be uniform, it should be recognized that a detected residue level may not represent the maximum amount that may be present. This is particularly true when surface sampling by swabs is performed on equipment.

The extent of microbiological controls needed for a given topical product will depend upon the nature of the product, the use of the product, and the potential hazard to users posed by microbial contamination. Pharmacopeia USP. It is therefore vital that manufacturers assess the health hazard of all organisms isolated from the product. Inspectional coverage should extend to microbiological control of deionized water systems used to produce purified water. Deionizers are usually excellent breeding areas for microorganisms.

The microbial population tends to increase as the length of time between deionizer service periods increases. Other factors which influence microbial growth include flow rates, temperature, surface area of resin beds and, of course, the microbial quality of the feed water. These factors should be considered in assessing the suitability of deionizing systems where microbial integrity of the product incorporating the purified water is significant.

From this assessment, a firm should be able to design a suitable routine water monitoring program and a program of other controls as necessary. It would be inappropriate for a firm to assess and monitor the suitability of a deionizer by relying solely upon representations of the deionizer manufacturer.

Specifically, product quality could be compromised if a firm had a deionizer serviced at intervals based not on validation studies, but rather on the "recharge" indicator built into the unit. Unfortunately, such indicators are not triggered by microbial population, but rather they are typically triggered by measures of electrical conductivity or resistance.