Transdermal gel drug therapy: fuss or must? (Proceedings)

Compounding of Drugs In Small Animals

Individualized drug therapy increasingly is being recognized as an important aspect of health care for both human and veterinary medicine. However, the number of animal drugs approved by the Food and Drug Administration (FDA) is sparse in comparison to those for human patients. Consequently, veterinarians must reach beyond FDA-approved veterinary products to provide the current standard of veterinary care to their patients. The lack of commercially - available drug formulations often leads the veterinarian to prescribe or dispense a product specifically designed and compounded for their patients' medical needs. Compounding has been defined by the National Association of Boards of Pharmacy (Model State Pharmacy Act) as the preparation, mixing, assembling, packaging, or labeling of a drug or device, as the result of a practitioner's prescription drug order (or initiative) and based on the practitioner /patient/pharmacist relationship (http://www.iacprx.org/index.html, accessed July 2004)

The last two descriptors – prescription driven and in the context of a veterinary (client) patient relationship- are vitally important but often unrecognized or ignored descriptors of the definition. Indeed, in 1997, the US Supreme Court itself has defined drug compounding as "a process by which a pharmacist or doctor combines, mixes, or alters ingredients to create a medication tailored to the needs of an individual patient." [Emphasis Id. at 361]. 1

Clearly, compounding is and always has been a critical component to the provision of individualized drug care to the small animal patient. The Animal Medicinal Drug Use Clarification Act guarantees the right of veterinarians to compound. However, the science and art of compounding are also guaranteed to pharmacists, a profession more properly trained in pharmaceutics (although not necessarily compounding). The sole justification for prescribing or dispensing a compounded preparation relates to the patient: no commercially available preparation is available which will meet the needs of the patient. Cost is NOT a justifiable reason for pursuing a compounded product. Many reasons exist for the veterinarian to use compounded products judiciously. These include legal and ethical reasons, all of which have been addressed in a comprehensive review of compounding for small animals (Vet Clin North Amer, in press; September 2006). Among the reasons are the lack of oversight by any state or (with the most recent federal court rulings) federal government oversite of the compounded product. Accordingly, no assurance can be provided regarding the quality, safety or efficacy of compounded product. Transdermal gels offer an example of both the best and worst considerations regarding the availability of novel drug delivery systems that are compounded.

Whereas approved animal or human drugs have undergone rigorous, scientific testing to ensure drug safety and efficacy for the patient, compounded products have not. Although pharmacists are directed to compound from written protocols and to maintain written records of compounding activities, currently pharmacists are not required to assure accuracy in product preparation, including product stability. Although a reputable pharmacy may randomly check accuracy of selected drugs, this act currently is voluntary and will be limited to selected drugs and aliquots. Although guidelines exist for establishing expiration dates of compounded products, dates are not necessarily based on scientific data and may not be followed. The risks associated with failed delivery (too much or too little) of a compounded product are added to risks associated with the approved finished dosing form of a drug. The more sophisticated the preparation, the more likely adverse events will occur because of diminished or excessive drug delivery.

Ingredient Errors

Compounding from bulk substances is easier than from approved finished dosing forms because excipients or other materials do not interfere with product preparations. Further, excipients in the finished dosing form will not interfere with dissolution of the drug in the vehicle. However, the use of an approved finished dosing form of a drug for compounding offers a major advantage to use of a bulk substance in that the approved drug has passed stringent tests of analysis regarding drug purity and potency, and the absence of contaminants. As such, products formed from bulk substances are associated with greater risks compared to products compounded from approved drugs because the approved version has passed stringent tests of analysis regarding drug ingredients and presence of contaminants. In contrast, for bulk substances, the burden of purity and accuracy lies with the pharmacist and there is no mechanism to assure that the burden has been met. All products, active ingredient or excipients (fillers, preservatives, etc), domestic or foreign, should either meet United States Pharmacopeia (USP) or equivalent standards; or should be purchased after FDA inspection. However, bulk substances increasingly are being acquired by compounding pharmacies from non-inspected foreign (particularly Asian) sources at a price much lower than their domestic counterparts. Drugs which are still under US patents are often obtained in this manner. Bulk substances will be accompanied by a credible certificate of analysis. The need for validation of ingredient source (including all active and inactive substances) is paramount as inexpensive bulk substances increasingly are being acquired from non-inspected foreign (particularly Asian) sources .

The active drug in a compounded product might also be substituted for an alternative drug; the substituted drug may not be characterized by the same pharmacokinetic or pharmacodynamic characteristics (also, see mathematical errors) and veterinarians should indicate on prescriptions that unapproved substitutions are not allowed for compounded products.

Mathematical Errors

Mathematical errors are probably the most common reason for pharmaceutical compounding errors, and potentially the most lethal. Compounding is predisposed to mathematical mistakes because, by its nature (prescription driven, small volumes), much of the equipment and technology that facilitates accuracy and precision of finished dosing forms is not (should not be) used. In addition to the source of the ingredient, pharmacists may substitute drugs without acquiring clinician permission. Mathematical errors may also reflect substitution of the active ingredient. For example, the content of active drug content may differ as is demonstrated by metronidazole. The recipe for metronidazole benzoate should contain 1.6 mg for each 1 mg metronidazole hydrochloride (or the dose must be similarly increased). Bromide offers another example: 1 gm of the sodium bromide contains more bromide (774 mg) than the potassium salt (692 mg).

Preparation and Storage Errors

Chemical reactions (oxidation, reduction, hydrolysis) are facilitated by changes in humidity, light, pH, presence of oxidizing trace metals, and increasing environmental temperature. 12,13 Excipients may enhance instability due to changes in pH or the presence of disintegrating agents. Degradation products (drugs or excipients) can cause adverse events. Excipients which are critical to the finished dosing form increase the risk of instability in product compounded from an approved source. Whereas approved products undergo intensive scrutiny in regards to stability and potency, compounded products do not; recipies for compounded preparations rarely are associated with studies that assure stability or delineate conditions for storage.

Simple syrups (which tend to be acidic), preservatives, combination drugs, or other ingredients can alter drug pH, and thus, ionization (diffusibility) or stability. The more drugs mixed together in a single preparation, the greater the risk of chemical drug interactions. For example, weak acids and weak basis are likely to chemically inactivate one another. Interactions may occur between the drugs or excipients. For example, only 54% of a fluorinated quinolone (orbifloxacin) was found to be present when prepared in Lixotinic® as a vehicle compared to simpler syrups.

Particle size. Compounding from approved drugs (legal) is more difficult than from bulk drugs (illegal) because excipients are more likely to result in undissolved macroscopic or microscopic precipitates which indicate undissolved and thus nondiffusible, ineffective drug. Sedimentation of undissolved particles may result in caking at the bottom of the drug receptacle; difficulty in shaking or rapid sedimentation (common) after shaking can result in erratic and unpredictable doses. Crushing of any oral tablet may result in unequal particle sizes in the preparation, which in turn will yield different surface areas and different rates of absorption. Fine crushing of the product such that it is no longer a suspension increases the concentration of soluble excipient ; chemicals, including those added to the finished dosing form to facilitate degradation, can cause drug instability. Crushing an oral tablet for preparation in a syrup may also lead to unequal distribution of dissolved drug in the finished preparation and mixing the drug such that it is equally distributed throughout the preparation may not be possible. Repackaging oral tablets or capsules into smaller dosing units may also impact drug efficacy. Diluents such as starch and dextrose might impede oral absorption. Preparation of an oral formulation from an injectable solution in order to enhance accuracy of dosing is more likely to be inappropriate if the drug salt is different between the preparations. If the injectable product is presented in powder form, the drug is likely to be unstable in liquids and may be destroyed when added to liquid (oral solutions). The addition of flavoring agents to oral products may increase drug instability due to changes in pH or the increased risk of microbial growth (ie, with syrups).

Selected commercial oral preparations have been formulated to alter (slow or facilitate) drug delivery and reformulation of such products should be avoided. Compounding altered release products from bulk substances requires sophisticated techniques not generally available through pharmacists. Enteric coated or spansule products should not be crushed. Although spansule products might be reformulated without crushing, the amount of drug in each spansule is not necessarily predicatable and random distribution of drug content is likely to yield erratic dosing. Cyclosporine is a complex molecule characterized by poor oral bioavailability; oral absorption requires bile acids or special formulation as a microemulsion product. As such, it is an example of a drug for which compounding should be approached cautiously, and be supported by therapeutic drug monitoring. In the author's drug monitoring laboratory, cyclosporine blood concentrations were not detectable (two different samples, two weeks apart) in one cat receiving a product compounded from an approved microemulsion human product. Following recommendations that the untampered animal approved version be used at the same dose, concentrations expected at the administered dose were detected within one week of the change in drug product.

Injectable products Administration of injectable products is inherently associated with a higher level of risk compared to administration of topical or oral products because of more rapid drug delivery, the risks associated with administration of suspensions rather than solutions, the potential impact of impurities (including endotoxin), and the need for sterility. Actions taken to assure sterility and removal of impurities may cause drug degradation. Endotoxin (which is essentially ubiquitous in the environment) is difficult to a remove. Without testing, its absence is impossible to document, yet, its presence can be lethal. The USP has generated guidelines and state laws generally delineate regulations specifically for the compounding of injectable products. Veterinarians should be reluctant to prescribe compounded injections and when doing so, must be confident that the compounding pharmacist follows these critieria.

Topical products. Although administration of topical products generally is associated with fewer risks compared to systemic products (the exception would be ophthalmic products, which also should be sterile), compounding the proper product can be challenging. The USP has promulgated guidelines for the compounding of topical ingredients, including guidelines are designed to assure drug dissolution and drug movement from the vehicle into the skin. For example, solid ingredients should be reduced to the smallest reasonable particles size and the active ingredient should then be added to other substances necessary to dissolve the drug in order to achieve a uniform liquid or solid dispersion. Uniformity of dispersion should be demonstrated by spreading a thin film of the finished formulation on a flat transparent surface. Visual examination of a compounded product should be implemented to identify obvious problems with dissolution, etc. Care must be taken to assure ingredients are not caustic, irritating, or allergenic Vehicle selection can be impressively difficult: undissolved drug can not pass into the skin; drug that has too great an affinity for the vehicle will remain in the vehicle. Transdermal gels offer an example where care must be taken with treatment of compounded preprations.

Few published reports exist that delineate adverse events resulting from inappropriate compounding. Despite indications of frequent problems with compounded products, the FDA receives few reports regarding adverse events related to compounded products. This reflects, in part, the lack of mandated adverse event reporting. However, it also reflects the difficulty in recognizing therapeutic failure due to failed delivery, The latter is likely to be detected only if it is sought and if the drug or response to the drug can be easily monitored. A variety of studies have focused on accuracy in labeling of compounded products, particularly in equine medicine. Products found to be mislabeled include omeprazole, ivermectin (both pirated drugs), ketoprofen (one product contained only 50% of the labeled content, whereas 12 of 13 contained close to 100%), amikacin (percent of labeled content ranged from 59 to 140%; none were within 10%), and boldenone (all within 15% of labeled content, but 2 of 5 contained up to 5% of impurities.

Transdermal Gels

Compounded transdermal pluronic-lethicin organo (PLO) gels have become a popular method of drug delivery widely embraced by the veterinary profession, despite the lack of scientific evidence in support of this system. The PLO gels were developed as a practical alternative to traditional drug delivery systems. Descriptions of the gels can not be found in the scientific literature but are limited to class materials and other non-referenced literature distributed to educators such as Professional Compounding Companies of America.e

The gels are comprised of water-based compounds prepared in various organic solvents. The oil phase is composed of lecithin (generally of soy bean origin) which theoretically re-arranges the stratum corneum, the major barrier to drug movement across the skin. Isopropyl palmitate acts as a solvent and penetration enhancer. The water phase is comprised of purified water and a pluronic (poloxamer) gel comprised of a surfactant (pluronic F127), which also contributes to disruption of the stratum corneum. Because lecithin promotes the growth of mold, potassium sorbate is included as a preservative.36 The active drug ingredient is dissolved in either the oil (lipid) or water phase, depending on its lipid solubility. The amount of active drug added is based on the recommended dose; generally, the gel is designed such that the dose is delivered in 0.1 ml (cats and small dogs) to 0.5 to 1 ml (larger dogs). Lecithin and isopropyl palmitate (a ratio of 1:1) must comprise at least 24% of the system in order for micelles containing the drug to form properly. The remaining volume of a PLO gel is comprised of the drug and the pluronic gel. Because manufactured drug preparations often are not available in concentrations sufficient to allow delivery of the calculated dose in the small volume of PLO, purified bulk powder (which is not legal) is preferred by compounding pharmacies formulating the gels. When subjected to proper shearing forces (generally accomplished by rapidly passing the mixture between a small caliber catheter or two syringes; Figure 3), micelles containing the drug theoretically are formed. The micelles are believed to slightly disorganize the stratum corneum with minimal direct detrimental effects on the skin (based on light microscopy), although contact hypersensitivity or allergy to the lecithin component may occur (see below).37, 38 The PLO gel is appears to dissolve a variety of different chemicals, including lipophilic, hydrophilic and amphoteric compounds. The gels can be easily and rapidly prepared and theotretically are stable in most clinic environments. However, the gels are thermoreversible: at temperatures above 40°C, they are liquid, but they become high-viscosity gels following cooling to room temperature and remixing. At refrigerated temperatures, the gels again become liquid. Thus, the PLO gel becomes more viscous at higher temperatures, rendering it more amenable to topical drug delivery.

At least two PLO gels (ie, with the pluronic and oil phases already mixed) are commercially available: Lipoderm® is sold by Professional Compounding Pharmacies of America (PCCA). This organization offers compounding training classes for pharmacists, including formulation of PLO gels and recipes for the preparation of many different drug products as gels. The advent of PLO gels as a method of systemic drug delivery and the formulation of the original PLO gel was generated through the PCCA division of research.e In addition to training, PCCA sells validated ingredients to be used in compounding. However, sale and compounding guidance is limited to PCCA members; membership at the time of publication of this article costs $20,000. The financial incentive for PCCA to train pharmacists in the compounding of PLO gels intended for veterinary use is obvious. Products for formulation of PLO gels are also available through other companies (eg, Gallipot which sells a commercial PLO base as well as drugs, and chemical companies which sell pure drugs). The products that PCCA offers for sale has drawn the attention of the Food and Drug Administration: a warning letter was sent in 2001 regarding their sale of bulk substances, including dipyrone and antibiotics.d

The availability of training in the preparation of PLO gels, and the level of promotion of gels by pharmacists suggests that this method of drug delivery has been validated scientifically. Yet, a review of the literature reveals little scientific support for the use of the PLO gel system and its ability to deliver drug. Despite the lack of scientific validity, the number of compounding pharmacies that are offering compounding services, including formulation of PLO gels, is increasing as training in their preparation continues (eg, at PCCA). Recipes for veterinary PLO gels have been published in the International Journal of Pharmaceutical Compounding, a journal whose articles tend to focus on the sharing of compounding information rather than the reporting of scientific studies. The list of PLO drug recipes for veterinary use is extensive and includes but is not limited to nonsteroidal antiinflammatories, antimicrobials, anticonvulsants, prokinetic agents, anticancer drugs, behavior modifying drugs, and hormones.e

The PLO gels offer other reasons that its use (as with other novel delivery systems) should be based on demonstrated efficacy using properly controlled studies. The site of administration is likely to vary among species and possibly among animals. Currently, PLO gels are applied to the ear so that grooming by the animal will not remove the drug. Although the stratum corneum of the inner ear is the thinnest in cats, it is the site of the thickest stratum corneum in dogs. The ability of a client to accurately administer 0.1 ml of a drug repetitively needs to be addressed; unpublished studies by our laboratory using clients of the Veterinary Teaching Hospital have found the actual volume administer by clients (using weighing paper) to range to range from 0.1 (the intended volume) to 1 ml.

The vehicle for most of these topical formulations is a soy lecithin based organic gel. Soy lecithin is a common allergen in people and has been reported to cause asthma and food allergies.18,19 A suspected adverse (allergic) reaction to a topical formulation of methimazole has been (Personal Communication, Katrina Mealey, Washington State University, April 2006) in a cat. Topical reaction has also been reported with multiple dosing following experimental use of the gel in cats19 The compounded PLO product also offers an example of increased risk of drug exposure to the veterinary client. Clients should wear non-permeable gloves when administering the drug and counseled regarding inappropriate exposure of the drug to children or other pets.

Design of dosing regimens using transdermal gels is complicated by the lack of knowledge regarding the impact of the stratum corneum on drug delivery. However, to assume that a transdermal drug is 100% bioavailable following transdermal delivery is optimistic at best and as such, transdermal doses probably should be increased compared to oral doses. This may also be true for drugs characterized by first pass metabolism for three reasons. Firstly, the skin can metabolize many drugs metabolized by the liver, although the extent of metabolism is likely to be less; but secondly, no study has yet to demonstrate greater than 10% bioavailability with a drug administered transdermally. As such, a drug characterized by 50% first pass metabolism might yet be only 20% bioavailable following transdermal delivery. Finally, for many of the drugs, metabolites are equally or more active than the parent compound and first pass metabolism may not impact efficacy.

Scientific data regarding the use of PLO gels for systemic drug delivery is slowly becoming available. Methimazole is among the most common drugs formulated in a PLO gel for administration in cats and may be the most likely drug to be successfully delivered as a PLO gel because of its small molecular weight of 115 (compared to >250 for most other drugs). Additionally, response to therapy can be monitored. A clinical abstract report (uncontrolled clinical trial) cited a response to methimazole administered as a PLO gel in 9/10 hyperthyroid cats based on decreased serum T4 concentrations39 Yet, an subsequent experimental report in normal cats following single dosing of methimazole as a PLO gel found the drug reached detectable concentrations in only 2 of 6 cats but was not quantifiable in the remaining 4 cats.40 A second abstract indicates that efficacy to methimazole as a PLO gel requires 4 weeks of therapy.41 Other studies have confirmed the failure of the PLO drug delivery system to achieve therapeutic concentrations (and often detectable) in cats following single dose administration. These include amikacin,d enrofloxacin (Figure 5)d , morphined , fentanyl,42 diltiazem,43 fluoxetine,44 buspirone and amitryptylline. 45 The pharmacy profession is beginning to self-educate regarding the applicability of PLO gel use.46 Clearly the need for follow-up studies focusing on multiple dosing with PLO gels is necessary; further, the use of the gels in situations in which immediate drug response is necessary should be strictly limited to use validated by science, or for drugs in which clinical response is clearly recognized either by monitoring, or the resolution of discreet, easily identifiable clinical signs.

We have recently completed a study of transdermal drug delivery in cats. All cats were client owned. All procedures were approved by the Institutional Animal Care and Use Committee at Auburn University. The study targeted 6 cats per drug; all were owned largely by students or staff of the College of Veterinary Medicine (CVM) at Auburn University. Owners were financially compensated for their cats participation and adherence to the study protocol. Cats were studied using a randomized, placebo-controlled, double blinded (owner and investigator), cross-over design (double crossover for prednisolone and prednisone) with one week washout between each treatment. All cats both forms of the drug for a 3 week period (not all cats tolerated the complete study, explaining n<6 for some drugs); cats receiving prednisone also received prednisolone via both routes (Table 2). All drugs were compounded save amitryptylline for which a commercial product was administered (Table 2 indicates target concentration of each prepration). All oral solutions (and gels) were compounded. Each cat received a placebo of the alternative route; thus, for each phase of crossover, each cat received both an oral solution and a PLO gel. All drugs were administered at 12 hour intervals.

All preparations were made prior to the start of each crossover, meaning each preparation was 3 weeks old by study end. All placebos were prepared exactly the same as the active drug, minus the drug. All drugs were prepared by the same pharmacist. Drugs were prepared from pure substrate rather than fixed dosing forms, thus facilitating homogenous drug distribution throughout the compounded preparation. To monitor strength, samples of both placebo and active drug were collected from each preparation for each cat at each blood sampling period (eg, 7, 14 and 21 days).

Dosing:

Because clinically transdermal gel doses are not modified to compensate for potential decreased bioavailability, the same dose was administered for either form of the drug (Table 2). Cats were dosed as close to 8 pm and 8 am for 21 days. The gels were prepared such that each cat received its calculated dose in 0.2 ml, with 0.1 ml applied to the internal pinna of each ear. Owners were directed to use latex gloves supplied by the investigators. In all cases, the volume of the placebo gel or a placebo solution was the same as the "active" preparation. All dosing save for the day of sample collection was performed by the owner in the home environment. Other than drug administration and travel to the study site on sampling days, all animals were handled as normal.

Table 2: Dosing and target information for gel and oral preparations

Conclusions

      1. Regarding administration of drug as a PLO gel: Methimazole is acceptable, buprenorphine may be acceptable (anticipate failure in 3 to 4/10 patients). Amitryptyline is acceptable only under extreme circumstances because it is characterized by marked variability and failure in 6 to 7/10 patients. Unacceptable drugs include prednisone, prednisolone, metronidazole, and enrofloxacin.

      2. Failure reflects concentrations that are too low but also is characterized by marked individual differences, with absorption being negligible in some cats but being acceptable in others.

      3. There is a need to identify methods by which inaccuracy and imprecision of oral and gel preparations is reduced.

      4. Oral prednisone is not a therapeutic option in cats.

      5. Oral metronidazole benzoate may not predictable achieve therapeutic concentrations in cats.

      6. Any or all drugs offered in as a PLO preparation should be studied in cats.

Conclusion

The advent and growth of veterinary compounding and the increasing role of the pharmacist in drug dispensing, including compounding, should be embraced by the veterinary profession. For selected patients, extemporaneous compounding of prescriptions is both necessary and beneficial for optimal treatment of veterinary patients. However, by its nature, compounding is individualized and fraught with risks of failure. Pet owners should be informed of the risks associated with using a compounded product and consent to therapy based on disclosure that the use of the product msay be scientifically unproven. The AVMA's Council on Biologic and Therapeutic Agents has generated a position statement regarding the use of compounded products which offers sage advice. The position statement reminds veterinarians that, although compounded products may have an important role in the treatment of veterinary patients, compounding may alter the ability of the product to delivery drug and compounding should be reserved for those instances in which there is a legitimate need, and, unless there is no alternative, for which evidence of efficacy or safety exists when administered as the compounded preparation. As the pharmacy profession increases its efforts to define and assure its role in veterinary medicine, and as the regulatory agencies consider changes in the regulations which increase the flexibility of animal drug compounding, the veterinary profession must "step up to the plate", and implement actions that will protect the patient and the public. Finally, although it is the responsibility of the pharmacist to assure the integrity of any finished drug product dispensed to a patient, as the pharmacists will point out when challenged for promoting a product whose scientific support is lacking, it indeed is the responsibility of the veterinarian to assure the safety and therapy of any prescribed therapeutic intervention, and failure to do otherwise places the patient and pet owner, as well as the veterinarian, at risk.

This manuscript represents a portion of the paper Boothe DM: Veterinary Compounding in Small

Animals: A Clinical Pharmacologist's Perspective published in Veterinary Clinics of North America, In press, September 2006; and Drug-Induced Disease, Small Animal Clinical Pharmacology and Therapeutics, Boothe DM.