TECHNOLOGY ADVANCEMENTS IN PASSIVE TRANSDERMAL DRUG DELIVERY SYSTEMS UTILIZING PRESSURE SENSITIVE ADHESIVES AND POLYMERIC COMPONENTS

David P. Kanios, Village of Palmetto Bay, FL Abstract The understanding of a pressure sensitive adhesives (PSAs) monomeric composition and the compositions interaction with drug(s) has enabled recent technology advancements during the formulation development stage for Passive Transdermal Drug Delivery Systems (TDDSs). Knowledge of the particular monomers comprising the PSA, their Glass Transition Temperature (Tg) and the ratio of the monomers in the composition has been shown to directly affect drug release from the TDDS and drug stability. As well as having an understanding of a PSA’s composition selected for product development, further knowledge of the drug-in-adhesive (DIA) matrix interaction with polymeric components comprising the backing films for TDDSs has also been shown to directly affect drug delivery and stability for the TDDS. Furthermore, by combining the knowledge base and understanding of the selected PSA(s) and backing film, novel and unique product development advancements have been attained in current passive TDDSs product development. Background Recent advancements have been made in the formulation of Passive Transdermal Drug Delivery Systems (TDDSs) by utilizing acrylic Pressure Sensitive Adhesives (PSAs) that are comprised of only two monomers and lack functional / reactive monomers. The monomers selected for the acrylic PSA composition vary only in their associated Glass Transition Temperature (Tg) and are referred to as either soft ( < - 10°C ) or hard ( > - 5°C ) monomers. The simple manipulation of the ratios between the two monomers has been shown to control the In-Vitro permeation rate and delivery profile of drugs from Passive TDDSs when the acrylic PSA is utilized either in the active Drug-In-Adhesive (DIA) matrix [ 1, 2 ] or as a component comprising the active DIA backing film [3, 4]. Furthermore, if small additions of a functional / reactive monomer is incorporated into the acrylic PSA comprising the backing film as previously mention, further manipulation and control of a drug’s In-Vitro permeation rate and delivery profile is made possible [ 3, 4, 5, 6]. Transdermal Drug Delivery System Matrix The primary Passive TDDS matrices explored in the following discussions and experimental designs is known in the art as a DIA TDDS. These TDDSs are comprised of a flexible backing film, an “active” adhesive composition, and a fluoropolymer release liner. The “active” adhesive is comprised of an acrylic PSA, a silicone PSA and drug [7]. Illustration 1 below is a simplified drawing of the aforementioned TDDS.

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Illustration 1: Drug-In-Adhesive TDDS Experimental Design The objective set out for the first experimental design was to compare Passive TDDSs utilizing acrylic PSAs with varying ratios of with two monomers, both having non-functionality and non- reactivity with drugs, for in-vitro drug delivery properties. Furthermore, all Passive TDDSs utilized for the backing study experimental design will also utilize a two monomer acrylic PSA composition in their DIA matrix. Individual case studies will be examined for each of the objectives listed above. Based on the data collected, discussion of results and conclusions will then be provided for each case study. Case Study I TDDSs Utilizing Varying Ratios of Hard and Soft Monomers Comprising Acrylic Adhesives In-vitro permeation studies were preformed to investigate the feasibility of utilizing acrylic pressure sensitive adhesives (PSAs), which are comprised of two varying monomer ratios, to control the permeation rate and delivery profile of hormones from Passive Transdermal Drug Delivery Systems (TDDSs). The monomers selected for the acrylic PSA composition varied in their associated Tg, and are referred to as either soft (< -10oC) or hard (> -5oC) monomers. The permeation studies were performed with TDDSs consisting of drug, acrylic PSA, silicone PSA, co-solvent(s) and polyvinylpyrrolidone (PVP) [7] [8]. The results of the studies conducted were both surprising and unexpected, but correlative to previous in-vitro studies conducted with d-Amphetamine Base [3], which utilized similar acrylic monomers comprising backing film layers. The results indicate manipulation of the permeation rate and delivery profile was determined to be induced by the acrylic PSAs monomer ratios, as historically seen by manipulation of the ratio between the acrylic PSA and silicone PSA concentrations in the drug-in-adhesive matrix. Finally, drug solubility in the drug-in-adhesive matrix was also noted to be influenced by the varying monomer ratios of the acrylic PSAs. Purpose

This investigation was initiated to establish formulary parameters for the delivery of hormones from TDDSs, which could then be utilized as a foundation for initiating future formulation development of

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other drugs in TDDSs. The parameters to be explored were drug permeation rate and delivery profile, as well as solubility, for a single drug-in-adhesive matrix. The hormone drug selected for incorporation into each drug-in-adhesive matrix was either a Estrogen, Progestin or Androgen. All in-vitro permeation studies were conducted without a control TDDS, as that the outcome of each experiment was strictly dependent on the monomeric composition of each acrylic PSA utilized for the particular study. Although the three parameters previously mentioned deal strictly with the individual drug, it was theorized the outcome of these studies would help define the future formulary work for similar and dissimilar active ingredients. Experimental Methods

A. Formulations

Drug Permeation / Profile : Study 1 Three non-functional / non-reactive acrylic PSAs, differing only in their monomer ratios, were formulated into a drug-in-adhesive matrix to determine which acrylic PSA controlled the permeation rate and delivery profile of Estrogen released from the TDDSs. The drug concentration was held at 2% while the silicone PSA to acrylic PSA ratio was 3:1 for the drug-in-adhesive matrix. The drug-in-adhesive matrix also included a unsaturated fatty alcohol and PVP at 6% and 10%, respectively. The dried drug-in-adhesive matrices had a coat weight of 10mg/cm2.

Drug Permeation / Profile : Study 2 Three non-functional / non-reactive acrylic PSAs, differing only in their monomer ratios, were formulated into a drug-in-adhesive matrix to determine which acrylic PSA controlled the permeation rate and delivery profile of Progestin released from the TDDSs. The drug concentration was held at 2% while the silicone PSA to acrylic PSA ratio was 3:1 for the drug-in-adhesive matrix. The drug-in-adhesive matrix also included a unsaturated fatty alcohol and PVP at 6% and 10%, respectively. The dried drug-in-adhesive matrices had coat weights of 10mg/cm2.

Drug Permeation / Profile : Study 3 Two non-functional / non-reactive acrylic PSAs, differing only in their monomer ratios, were formulated into a drug-in-adhesive matrix to determine which acrylic PSA controlled the permeation rate and delivery profile of Androgen released from the TDDSs. The drug concentration was held at 2%, while the silicone PSA and acrylic PSA ratio was 4:3 for the drug-in adhesive matrix. Each drug-in-adhesive matrix also included an unsaturated fatty alcohol, a dihydric alcohol and PVP at 6%, 8% and 10%, respectively. The dried drug in-adhesive matrices had coat weights of 10mg/cm2.

B. In-Vitro Permeation Studies

Determination of the permeation properties of the described formulations were conducted on a modified Franz Diffusion Cell through a disc of stratum corneum obtained from human cadaver skin. The formulations were die punched, mounted on the disc, and placed on the cell, which contained an isotonic saline solution. The cells were stored at 32!C for the duration of each permeation study while having the solution stirred at a constant rate of approximately 300 rpm. Samples of the solution were taken during the course of each study (approximately 72 hours) to

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determine the permeation characteristics for each formulation. The drug concentrations in each cell were determined by HPLC. Finally, all formulations were run with a population of n=5 for each permeation study.

Discussion of Results A. Drug Permeation / Profile : Study 1

Figure 1 illustrates the graphical representation of the results for the three non-functional/non-reactive acrylic PSAs incorporated into the drug-in-adhesive TDDSs and their effect on the in-vitro delivery of an Estrogen drug. The three acrylic PSAs were comprised of polymerized hard and soft non-functional monomers in ratios of 3:7, 1:1 and 4:1. It was surmised that no effect should have been noted in the delivery profiles between three acrylic PSAs utilized in the TDDSs based on their non-reactive properties and total solubility for the drug at 2% concentration. Further investigations will need to be conducted to explore the cause and effect of the “dump and die” profile caused by the higher amount of the soft acrylic monomer (70%) in the acrylic PSA composition compared to the similar results obtained from the 1:1 and 1:4 ratios of soft to hard monomers comprising the two other acrylic PSAs. Finally, future in-vitro permeation investigation will be required to determine whether the non-zero order delivery profiles of all three platforms is formulary or drug concentration dependent.

Figure 1.

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B. Drug Permeation / Profile : Study 2

Based on the results of Study 1, Study 2 was conducted to investigate the permeation rate and delivery profile of a Progestin drug when incorporated into the same drug-in-adhesive matrices. Figure 2 illustrates the permeation profile for the three formulations. Similar to the previous results illustrated in Study 1, the use of a higher amount of soft monomer (70%) in the acrylic PSA composition resulted in a higher permeation of the drug. Furthermore, similar in-vitro permeation profiles were obtained with either the 1:1 or 4:1 ratios of hard to soft monomers comprising the acrylic PSA composition. Finally, the results of Study 2 indicate that all three drug-in-adhesive matrices rendered near zero order delivery profiles regardless of the acrylic PSA monomeric composition.

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C. Drug Permeation / Profile : Study 3

Figure 3 illustrates the permeation rate and delivery profile for variation of soft and hard monomers comprising two acrylic PSAs utilized in Studies 1 and 2, with an Androgen as the drug. The graphical presentation indicates that permeation rate of the drug increases with the higher amount of hard monomer, while the delivery profile approaches near-zero order and lower permeation as the soft monomer increases in the acrylic PSA. The results of this study are inverse of those attained from the use of Estrogen or Progestin as the incorporated drug in the active adhesive matrix.

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Figure 3.

Conclusion The results of the three in-vitro permeation studies indicate compositional manipulation of the acrylic PSA allows flexibility to attain a desired permeation rate and delivery profile for the drugs selected. Utilizing acrylic PSAs, comprised of two differing Tg monomers, enhances the experimental design with which the formulator can develop TDDSs. As previously discussed, the three parameters evaluated were drug permeation rate, delivery profile and solubility. All explored studies results suggest the simple manipulation of monomeric ratios, in the composition of the acrylic PSAs, influences both the permeation rate and delivery profile of the drug from the TDDS. A visual evaluation of each studies drug to recrystallize (exposed atmospheric condition) in the drug-in-adhesive matrix indicated that i) Studies 1 and 2 TDDSs had no observed crystals after 28 days and ii) Study 3 TDDSs had crystals in the 1:1 hard to soft monomer ratio composition of the acrylic PSA, while the 4:1 ratio of hard to soft monomer ratio acrylic PSA was crystal free after 28 days. These results indicate that further evaluation is needed to determine individual drug saturation points in each acrylic PSA comprised of only hard and soft monomers.

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Case Study II TDDSs Utilizing Acrylic Polymer Backing Films

In-vitro permeation studies were preformed to investigate the feasibility of utilizing backing films comprised of polyester (PET) and acrylic polymers to control the permeation rate and delivery profile for Passive Transdermal Drug Delivery Systems (TDDSs). The base form of d-Amphetamine was the drug selected for this investigation. The permeation studies were performed with TDDSs consisting of drug, acrylic pressure sensitive adhesive (PSA), and silicone PSA [7][9]. The results of the studies conducted were both surprising and unexpected, but correlative to previous in-vitro studies conducted with both Methylphenidate Base [10][8] and d-Amphetamine Base [11]. For these studies, the in-vitro permeation profiles for matrices laminated to the acrylic polymer side of the backing, particularly those with non-functional / non-reactive moieties, resulted in both faster on-set and diminished sustained drug release. Further manipulation of the permeation rate and delivery profile was determined to be induced by the acrylic polymer moiety of the backing, as historically seen by manipulation of the ratio between the acrylic PSA and silicone PSA concentrations in the drug-in-adhesive matrix. Finally, the acrylic polymer thickness, noted as coat weight, of the composite backing film also influenced the permeation rate of the drug from the TDDS. Purpose This investigation was initiated to establish formulary parameters for the delivery of d-Amphetamine from TDDSs, which could be utilized in the treatment of Attention Deficit Hyperactivity Disorder (ADHD). The parameters to be explored were drug permeation rate and delivery profile, as well as on-set (lag time), for a single drug-in-adhesive matrix, which was laminated to various backing films comprised of PET and acrylic polymers. The drug-in-adhesive matrix consisted of d-Amphetamine, acrylic PSA and silicone PSA. All in-vitro permeation studies were conducted against a control TDDS, Methylphenidate Transdermal System (MTS). Although the three parameters previously mentioned need to be defined for “in-vivo” studies for the drug under investigation, it was theorized the outcome of these studies would help define the final formulary for clinical studies.

Experimental Methods

A. Formulations

Drug Permeation / Profile : Study 1 Two non-functional / non-reactive acrylic polymer backings, differing only in their monomer ratios, were laminated to a drug-in-adhesive matrix to determine which acrylic polymer controlled the permeation rate and delivery profile of d-Amphetamine released from the TDDSs. The drug concentration was held at 20% while the silicone PSA to acrylic PSA ratio was 15:1 for the drug-in-adhesive matrix. The MTS was utilized as a control for the study. The acrylic polymer of the backing had a coat weight of 7.5mg/cm2.

Drug Permeation / Profile : Study 2 Three acrylic polymer backings were laminated to the drug-in-adhesive matrix as described in Study 1. The three acrylic polymer backings utilized varying concentrations of acrylic acid in their

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composition. The objective of this study was to determine acrylic reactivity and its influence on permeation rate and delivery profile of d-Amphetamine from the TDDSs. The MTS was utilized as a control for the study. The acrylic polymer of the backing had a coat weight of 7.5mg/cm2.

Drug Permeation / Profile : Study 3

A single acrylic polymer backing, with three coat weights (2.5mg/cm2, 5.0mg/cm2, 7.5mg/cm2), were laminated to the drug-in-adhesive matrix as described in Study 1. The objective was to determine if backing thickness had an influence on permeation rate and delivery profile of d-Amphetamine from the TDDSs. The MTS was utilized as a control for the study. All formulations utilized for the experimental design had dried drug-in-adhesive coat weights of approximately 5.0 mg/cm2.

B. In-Vitro Permeation Studies

Determination of the permeation properties of the described formulations were conducted on a modified Franz Diffusion Cell through a disc of stratum corneum obtained from human cadaver skin. The formulations were die punched, mounted on the disc, and placed on the cell, which contained an isotonic saline solution. The cells were stored at 32!C for the duration of each permeation study while having the solution stirred at a constant rate of approximately 300 rpm. Samples of the solution were taken during the course of each study (approximately 9 hours) to determine the permeation characteristics for each formulation. The d-Amphetamine and Methylphenidate concentrations in each cell were determined by HPLC. Finally, all formulations were run in sets of n=5 for each permeation study.

Discussion of Results A. Drug Permeation / Profile : Study 1

Figure 1 illustrates the graphical representation of the results for the two non-functional/non-reactive acrylic polymer backings and their effect on the delivery of d-Amphetamine. The two acrylic backing layers were comprised of polymerized hard and soft non-functional monomers in ratios of 1:1 and 8:2. It was surmised that no effect should have been noted in the delivery profiles between the two backings based on their non-reactive properties with the drug. Further investigations will need to be conducted to explore the cause and effect of the “dump and die” profile caused by the higher amount of the hard acrylic monomer in the backing composition.

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Figure 1. B. Drug Permeation / Profile : Study 2

Based on the results of Study 1, Study 2 was conducted to investigate the permeation rate and delivery profile of d-Amphetamine when utilizing various amounts of carboxy functional monomer in the acrylic backing. Figure 2 illustrates the permeation profile for the three formulations. The non-functional acrylic backing imparted the fastest on-set and highest depletion of d-Amphetamine when compared to the two acrylic backings comprised of either 4% or 8% carboxy functional monomer. Furthermore, the addition of the carboxy functional monomer into the acrylic backing decreased the drug on-set and provided a near zero-order delivery profile. These results determined the delivery profile and on-set could be controlled by manipulating the acrylic backing moiety.

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Figure 2. C. Drug Permeation / Profile: Study 3

Figure 3 illustrates the permeation rate and delivery profile for variation of acrylic backing coat weights, utilizing the 8% carboxy functional backing from Study 2. The graphical presentation indicates that permeation rate increases as the backing film thickness decreases, while the delivery profile approaches near-zero order as the acrylic backing thickness increases. Further investigation is required to determine if the same or different attributes are resultant from the use of acrylic backings described in Study 1.

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Figure 3. Conclusion The results of the three in-vitro permeation studies indicate compositional manipulation of the acrylic backing polymer (monomer, moiety, thickness) allows flexibility to attain a desired permeation rate and delivery profile for d-Amphetamine. Utilizing acrylic polymers in backing films enhances the experimental design with which the formulator can develop TDDSs. As previously discussed, the three parameters evaluated were drug permeation rate, delivery profile and on-set. Study 1 results suggest the simple manipulation of monomeric ratios, in the composition of the acrylic polymers, influences both the permeation rate and delivery profile of the drug from the TDDS. Study 2 indicates the addition of functional moiety, carboxy, in increasing increments diminishes both permeation rate and on-set, but can provide a near-zero order delivery profile. Finally, Study 3 results indicate both the permeation rate and delivery profile can also be greatly influence by simply adjusting the total thickness of the acrylic polymer backing. The three in-vitro permeation/profile studies imply the choice of a non-functional/non-reactive acrylic polymer for the backing, with variations in thickness, would allow the highest flexibility for controlling the permeation rate, delivery profile and on-set of d-Amphetamine depending on the release profile required for therapeutic delivery. Furthermore, this same experimental design has been conducted with other drug entities, to verify and confirm applicability for other TDDSs.

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General Discussion / Conclusion The two case studies presented clearly have shown that simplicity is offered for the formulation of Passive TDDSs by utilizing acrylic PSAs comprised of only two monomers. By varying the ratios between a soft and hard monomer in the acrylic PSA composition, one can control both the permeation rate and release profile of the drug from the TDDS. When selection of an acrylic PSA was for the DIA matrix, the monomer ratio also influenced drug solubility. Crystallization drugs in TDDSs matrices over time directly results in a lower permeation rate and a change in the release profile for commercial products; as such, products that exhibit drug crystallization are often subject to product recalls. Finally, the use of two part acrylic PSAs, or those with small amounts of monomers with functionality, for backing film compositions clearly shows that opportunities exist in the field as an alternative to co-extruded films. Acknowledgments I would like to thank Noven Pharmaceuticals, Inc., Miami, FL, for supporting the time and research efforts that have gone into this presentation. Furthermore, I would also like to extend appreciation to my former colleagues at Noven for their support throughout the years and all contributions pertaining to this writing. Finally, I am also indebted to the adhesives, fine chemical and film industries for their supportive nature in open dialogue and education shown throughout the years. References [1] Kanios D., Hartwig R., Nguyen V., Bonne S.; In-Vitro Permeation and Delivery Profile from Transdermal Drug Delivery Systems Utilizing varying Ratios of Hard and Soft Monomers Comprising Acrylic Adhesives; AAPS 2004 [2] Kanios D.; Device for Transdermal Administration of Drugs Including Acrylic Polymers; US Patent App. 2006/0078602 A1 [3] Kanios D., Hartwig R., Adams R.; Controlled In-Vitro Permeation and Profile from Transdermal Drug Delivery Systems Utilizing Acrylic Polymer Backing Films; AAPS 2003 [4] Kanios D., Hartwig R., Mantelle J., Houze D.; Composition and Methods for Controlling Drug Loss and Delivery in Transdermal Drug Delivery Systems; US Patent App. 2005/0169977 [5] Hartwig R., Kanios D., Bonne S.; Acrylic Polymer Backing Films for Controlling In-Vitro Permeation and Delivery Profile of Estradiol from Transdermal Drug Delivery Systems; AAPS 2004 [6] Kanios D., Hartwig R.; Composition and Method for Delivering Estradiol in Transdermal Drug Delivery Systems; US Patent App. 2006/007801 A1

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[7] Miranda J., Sablotsky S.; Solubility Parameter Based Drug Delivery System and Method for Altering Drug Saturation Concentration; US Patent 5,474,783 [8] Kanios D., Hartwig R.; Effect of Non-Functional / Non-Reactive Pressure Sensitive Adhesives in Transdermal Drug Delivery Systems; PSTC Tech XXVI Proceedings 2003 [9] Woodard J., Metevia V.; Transdermal Drug Delivery Devices with Amine- Resistant Silicone Adhesives; US Patent 4,655,767 [10] Kanios D., Mantelle J.; Delivery Optimized Thermodynamics in Methylphenidate Transdermal Drug-In-Adhesive Systems; AAPS 2000 [11] Kanios D., Hartwig R., Moncada K.; In-Vitro Permeation Performance of Low Molecular Weight Amine Drugs in Transdermal Drug Delivery Systems; AAPS 2002

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TECH 32 Technical Seminar Speaker Technology Advancements in Passive Transdermal Drug Delivery Systems Utilizing Pressure Sensitive Adhesives and Polymeric Components David P. Kanios, Consultant

David P. Kanios is currently an outside consultant for Noven Pharmaceuticals, Inc., Miami, FL. Prior to January 2009, Kanios was director – research & development at Noven where he had been involved with product development, process development, product scale-up and commercial manufacturing of transdermals and transoral products since 1994. Past employment experience includes new product development at Space Labs Medical in Seattle, WA from 1991 to 1994 for hospital monitoring devices. Kanios began his career in adhesives while attending the University of Akron, with studies in civil engineering and mathematics, at Adhesive Consultants, Inc. in Akron, Ohio where he was employed from 1981 until 1990. He can be reached at dkanios@att.net.

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