Patent Application
20080286349
1. Field of Technology
This disclosure generally relates to the field of topical and transdermal administration of active agents and, more particularly, to systems, devices, and methods for transdermally delivering active agents to a biological interface via passive diffusion.
2. Description of the Related Art
Conventionally administered active agents in the form of, for example, capsules, injectables, ointments, and pills are typically introduced into the body as pulses that usually produce large fluctuations of active agent concentrations in the bloodstream and tissues and, consequently, provide unfavorable patterns of efficacy and toxicity. For example, conventionally administered active agents for obstructive respiratory aliment treatments generally include inhalation aerosols and inhalation solutions typically administered using inhaler devices (e.g., inhalers). Typically, inhaler devices have an active agent, medication, or drug stored in solution, in a pressurized canister, which is attached to a manually actuated pump. To use a standard inhaler device, a user must first exhale, then insert a mouth-piece end of the inhaler device in their mouth, then manually actuate the pump of the inhaler device while retaining the mouth-piece end in their mouth, and then the user may have to hold their breath for a prerequisite amount of time so that the active agent or medication or drug has a chance to be absorbed into the body instead of being exhaled from the user. Some users may find inhaler devices difficult to use. For example, a user of an inhaler device needs the ability to physically manipulate and actuate the inhaler device. Young users or feeble users may have difficulty mustering the coordination necessary to properly use an inhaler device. Additionally, users lacking the ability to hold their breath for the prerequisite time may likewise be unable to take advantage of inhaler devices.
Accordingly, a need exists for providing alternative modes for administering active agents, for example using transdermal delivery devices, to treat obstructive respiratory ailments.
Skin, the largest organ of the human body, offers a painless and compliant interface for systemic drug administration. As compared with injections and oral delivery routes, transdermal drug delivery increases patient compliance, avoids metabolism by the liver, and provides sustained and controlled delivery over long time periods. Transdermal delivery may in some instances, increase the therapeutic value by obviating specific problems associate with an active agent such as, for example, gastrointestinal irritation, low absorption, decomposition due to first-pass effect (or first-pass metabolism or hepatic effect), formation of metabolites that cause side effects, and short half-life necessitating frequent dosing.
Although skin is one of the most extensive and readily accessible organs, it is relatively thick and structurally complex. Thus, it has historically been difficult to deliver certain active agents transdermally. To transport through intact skin into the blood stream or lymph channels, the active agent must penetrate multiple and complex layers of tissues, including the stratum corneum (i.e., the outermost layer of the epidermis), the viable epidermis, the papillary dermis, and the capillary walls. It is generally believed that the stratum corneum, which consists of flattened cells embedded in a matrix of lipids, presents the primary barrier to absorption of topical compositions or transdermally administered drugs.
Due to the lipophilicity of the skin, water-soluble or hydrophilic drugs are expected to diffuse more slowly than lipophilic drugs. While lipid-based permeation enhancers (such as hydrophobic organic substances including vegetable oils) can sometimes improve the rate of diffusion, such permeation enhancers do not mix well with hydrophilic drugs. For example, development of a transdermal vehicle for delivery of Procaterol, a bronchial dilator, has faced numerous difficulties. Procaterol is highly hydrophilic, and delivery through the skin has not been possible when combined with hydrophobic organic substances.
Commercial acceptance of transdermal delivery devices or pharmaceutically acceptable vehicles is dependent on a variety of factors including cost to manufacture, shelf life, stability during storage, efficiency and/or timeliness of active agent delivery, biological capability, and/or disposal issues. Commercial acceptance of transdermal delivery devices or pharmaceutically acceptable vehicles is also dependent on their versatility and ease-of-use.
The present disclosure is directed to overcoming one or more of the shortcomings set forth above, and/or providing further related advantages.
Transdermal delivery devices and topical formulations are described. In various embodiments, ionizable and ionized active agents can passively permeate through skin to reach the blood stream and ultimately be delivered systemically.
One embodiment describes a passive transdermal delivery device comprising: a backing substrate; and an active agent layer, wherein the active agent layer is substantially anhydrous and oil-free and includes a thickening agent and an ionizable active agent, and wherein the ionizable active agent is electrically neutral in the active agent layer and dissociates into an ionized active agent upon contacting an aqueous medium.
A further embodiment describes a topical formulation comprising: a thickening agent, an ionized active agent; and an aqueous medium, wherein the topical formulation is substantially oil-free.
Yet another embodiment describes a method of treating a condition associated with an obstructive respiratory ailment in a subject comprising: applying to the subject's skin a passive transdermal delivery device comprising: a backing substrate; and an active agent layer, wherein the active agent layer is substantially anhydrous and oil-free and includes a thickening agent and an ionizable active agent, and wherein the ionizable active agent is electrically neutral in the active agent layer and dissociates into an ionized active agent upon contacting an aqueous medium; and allowing the ionizable active agent to dissociate into the ionized active agent.
In the drawings, identical reference numbers identify similar elements or acts. The sizes and relative positions of elements in the drawings are not necessarily drawn to scale. For example, the shapes of various elements and angles are not drawn to scale, and some of these elements are arbitrarily enlarged and positioned to improve drawing legibility. Further, the particular shapes of the elements, as drawn, are not intended to convey any information regarding the actual shape of the particular elements, and have been solely selected for ease of recognition in the drawings.
In the following description, certain specific details are included to provide a thorough understanding of various disclosed embodiments. One skilled in the relevant art, however, will recognize that embodiments may be practiced without one or more of these specific details, or with other methods, components, materials, etc. In other instances, well-known structures associated with delivery devices including, but not limited to, protective coverings and/or liners to protect delivery devices during shipping and storage have not been shown or described in detail to avoid unnecessarily obscuring descriptions of the embodiments.
Unless the context requires otherwise, throughout the specification and claims which follow, the word “comprise” and variations thereof, such as, “comprises” and “comprising” are to be construed in an open, inclusive sense, that is as “including, but not limited to.”
Reference throughout this specification to “one embodiment,” or “an embodiment,” or “in another embodiment,” or “in some embodiments” means that a particular referent feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment. Thus, the appearance of the phrases “in one embodiment,” or “in an embodiment” or “in another embodiment,” or “in some embodiments” in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments.
It should be noted that, as used in this specification and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the content clearly dictates otherwise. Thus, for example, reference to an active agent includes a single active agent, or two or more active agents. It should also be noted that the term “or” is generally employed in its sense including “and/or” unless the content clearly dictates otherwise.
It is conventionally believed that ionic drugs do not easily permeate through the skin and are generally not suited for topical formulations (e.g., creams and lotions) or transdermal patches. However, according to the various embodiments described herein, certain ionizable active agents are capable of permeating skin and entering into blood stream or lymph channels. Based on both theoretical models and empirical results of ion permeation within the skin, it is described herein a logical approach to designing transdermal delivery devices (e.g., patches) and topical formulations to passively deliver an ionized active agent. Also described are methods of making and using the same.
One embodiment provides a passive transdermal delivery device, such as a transdermal patch, comprising a backing substrate and an active agent layer, wherein the active agent layer is substantially anhydrous and oil-free and includes a thickening agent and an ionizable active agent, and wherein the ionizable active agent is electrically neutral in the active agent layer and dissociates into an ionized active agent upon contacting an aqueous medium.
As used herein, “transdermal delivery” refers to passive diffusion of ionic active agents in the absence of externally-applied electrical current. However, as a result of diffusion through skin, the ionic substances establish a concentration gradient, which can give rise to an electrical potential difference on either side of the skin. The electrical potential difference may speed up or hamper the ionic diffusion process, depending on a host of interrelating factors, including the velocity, flux and size of the various ions. It is discussed herein that ionic passive diffusion under controlled conditions can benefit from the dual effects of the electrical potential as well as the concentration gradient.
The optional base layer 14a may be constructed out of any suitable material including, for example, polymers, thermoplastic polymer resins (e.g., poly(ethylene terephthalate)), and the like. In some embodiments, the optional base layer 14a and the active agent layer 16a may cover a substantial portion of the backing substrate 12a. For example, in some embodiments, the backing substrate 12a, the optional base layer 14a, and the active agent layer 16a may be disk shaped and the backing substrate 12a may have a diameter of approximately 15 millimeter (mm) and the optional base layer 14a and the active agent layer 16a may have respective diameters of approximately 12 mm. In some embodiments, the sizes of the backing substrate 12a, the base layer 14a, and the active agent layer 16a may be larger or smaller, and in some embodiments, the relative size differences between the backing substrate 12a, the base layer 14a, and the active agent layer 16a may be different from that shown in
The delivery device 10b includes, a backing substrate 12b, a base layer 14b, and an active agent layer 16b storing one or more ionizable active agents. It has been found that replenishing the ionizable active agent in the active layer 16b may play an important roll for proper delivery of the active agent. In particular, by replenishing the ionizable active agent in the active agent layer 16b (or 16a), it is possible to maintain a concentration of the ionizable active agent in the active agent layer 16b (or 16a) that is fairly or substantially constant over time. Accordingly, in the embodiment illustrated in
In various embodiments, the active agent layer 16a includes a thickening agent and a therapeutically effective amount of an ionizable active agent.
“Thickening agent” refers to an inert and viscous material that provides the bulk of the active agent layer. For example, the thickening agent provides a sol into which the active agent is dispersed. By adjusting the relative amounts of the thickening agent and the active agent, active agent layers of selected concentrations and viscosities can be prepared. Typically, the thickening agent is a cellulose derivative. Exemplary thickening agents include, but are not limited to, polysaccharides (e.g., hydroxypropyl cellulose, hydroxymethyl cellulose, hydroxypropyl methylcellulose and the like) proteins, viscosity enhancers, and the like.
“Active agent” refers to a compound, molecule, or treatment that elicits a biological response from any host, animal, vertebrate, or invertebrate, including, but not limited to, fish, mammals, amphibians, reptiles, birds, and humans. Non-limiting examples of an active agent includes a therapeutic agent, a pharmaceutical agent, a pharmaceutical (e.g., a drug, a therapeutic compound, a pharmaceutical salt, and the like), a non-pharmaceutical (e.g., a cosmetic substance, and the like), a vaccine, an immunological agent, a local or general anesthetic or painkiller, an antigen or a protein or peptide such as insulin, a chemotherapy agent, and an anti-tumor agent.
An ionizable active agent refers to an active agent, as defined herein, that is electrically neutral (i.e., non-ionized) prior to contacting an aqueous medium. Upon contacting an aqueous medium, the ionizable active agent dissociates into an “ionized active agent” and a counterion. Depending on the chemical structure of the ionizable active agent, the ionized active agent can be cationic or anionic. As used herein, an aqueous medium refers to a water-containing environment, including moisture, aqueous solution (e.g., saline solution), and sweat present on skin.
Typically, the ionizable active agent is a salt. In certain embodiments, an active agent containing one or more amines (including primary, secondary and tertiary amine) or imines can be converted into an ionizable salt form in the presence of an acid. Preferably, the active agent has a tertiary amine or secondary amine and the acid is a strong acid such as hydrochloride acid (HCl). The salt dissociates into a cationic active agent (containing a positively-charged ammonium ion) and a counter ion (e.g., chloride). Thus, the acid (organic or inorganic) is selected such that the counter ion is physiologically compatible. Exemplary acids include, for example, phosphoric acid (phosphate counterion), citric acid (citrate counterion), acetic acid (acetate counterion), lactic acid (lactate counterion) and so forth.
Thus, in certain embodiments, the ionizable active agent that produces a cationic active agent is an amine-containing drug. In one embodiment, the active agent layer includes Procaterol as a pharmaceutically acceptable salt, i.e., 8-hydroxy-5-[1-hydroxy-2-[(1-methylethyl)amino]butyl]-2(1H)-quinolinone, [(R*,S*)-(+−)-8-hydroxy-5-(1-hydroxy-2-((1-methylethyl)amino)butyl)-2(1H)-quinolinone] as a pharmaceutically acceptable salt. See, e.g., U.S. Pat. No. 4,026,897 which is hereby incorporated by reference in its entirety. Suitable salt forms of Procaterol include Procaterol HCl and its hydrate forms, including Procaterol HCl hemihydrate, Procaterol HCl hydrate, and respective isomers thereof:
Procaterol is one example of a class of amine-containing β-adrenergic agonists. Other examples of amine-containing β-adrenergic agonists include Arformoterol, Bambuterol, Bitolterol, Clenbuterol, Fenoterol, Formoterol, Hexoprenaline, Isoetarine, Levosalbutamol, Orciprenaline, Pirbuterol, Procaterol, Reproterol, Rimiterol, Salbutamol, Salmeterol, Terbutaline, Tretoquinol, Tulobuterol, and the like.
In further embodiments, the amine-containing ionizable active agent is a “caine”-type analgesic or anesthetic. In particular, the ionizable active agent is a salt form of Lidocaine, e.g., Lidocaine HCl. Other amine-containing “caine” type drugs include, for example, centbucridine, tetracaine, Novocaine® (procaine), ambucaine, amolanone, amylcaine, benoxinate, betoxycaine, carticaine, chloroprocaine, cocaethylene, cyclomethycaine, butethamine, butoxycaine, carticaine, dibucaine, dimethisoquin, dimethocaine, diperodon, dyclonine, ecogonidine, ecognine, euprocin, fenalcomine, formocaine, hexylcaine, hydroxyteteracaine, leucinocaine, levoxadrol, metabutoxycaine, myrtecaine, butamben, bupivicaine, mepivacaine, beta-adrenoceptor antagonists, opioid analgesics, butanilicaine, ethyl aminobenzoate, fomocine, hydroxyprocaine, isobutyl p-aminobenzoate, naepaine, octacaine, orthocaine, oxethazaine, parenthoxycaine, phenacine, piperocaine, polidocanol, pramoxine, prilocaine, propanocaine, proparacaine, propipocaine, pseudococaine, pyrrocaine, salicyl alcohol, parethyoxycaine, piridocaine, risocaine, tolycaine, trimecaine, tetracaine, anticonvulsants, antihistamines, articaine, cocaine, procaine, amethocaine, chloroprocaine, marcaine, chloroprocaine, etidocaine, prilocaine, lignocaine, benzocaine, zolamine, ropivacaine, dibucaine, as pharmaceutically acceptable salt thereof, or mixtures thereof.
In other embodiments, the ionizable active agent contains one or more carboxylic acids (—COOH), which can be in a salt form. This type of ionizable active agent dissociates into anionic active agent and a physiologically compatible counterion. For example, in certain embodiments, the ionizable active agent is an alkaline salt of Diclofenac. Diclofenac is a non-steroidal anti-inflammatory drug (NSAID). The sodium salt of Diclofenac (i.e., monosodium 2-(2-(2,6-dichlorophenylamino)phenyl)acetate) has the following general molecular formula:
Other suitable physiologically-compatible counterions include, for example, ammonium, potassium and so forth.
In other embodiments, the ionizable active agent is a salt of ascorbic acid or a derivative thereof. Ascorbic acid is an antioxidant and inhibits melanogenesis. Its salt form can dissociate into ascorbate anion and a positively charged counterion. For example, the sodium salt of ascorbic acid (or sodium ascorbate in L or D form) is shown below:
In certain embodiments, the ionizable active agent is a stable ascorbic acid derivative: L-Ascorbic acid 2-Glucoside (AA2G) dissociates into AA2G (−) and a proton.
In some instances, once permeate into the skin, ionized active agents can rapidly depart from the lipophilic bilayers in the skin and reach deeper into the tissue, and ultimately reach the blood stream and deliver systemically.
Polarizable active agents are also within the scope of suitable active agents. “Polarizable active agent” is also electrically neutral but exhibits more polarity at one portion relative to another portion in the presence of a polar solvent (such as an aqueous medium, as defined herein).
In addition to the thickening agent and the ionizable active agent, the active agent layer 16a may further include one or more optional components such as an ionizable additive, a humectant, a plasticizer and a permeation enhancer.
“Ionizable additive” refers to an inert salt that produces ions upon contact with an aqueous medium. As discussed in more detail herein, the ionizable additive dissociated ions that contribute to the formation of concentration gradient and influence the electrical potential induced by ion flux during the ionic permeation process. Advantageously, based on their permeation characteristics, suitable ionizable additive can be selected to aid the permeation process of the ionized active agent. Exemplary ionizable additives include potassium chloride (KCl), sodium chloride (NaCl), and the like.
In some embodiments, the active agent layer 16a may include a humectant. Exemplary humectants include, but are not limited to, hygroscopic substances, molecules having several hydrophilic groups (e.g., hydroxyl groups, amines groups, carboxyl groups, esterified carboxyl groups, and the like), compounds having an affinity to form hydrogen bonds with water molecules, and the like. Further examples of humectants include, but are not limited to, urea, glycerine, propylene glycol (E 1520) and glyceryl triacetate (E1518), polyols (e.g., sorbitol (E420), xylitol and maltitol (E965), polymeric polyols (e.g., polydextrose (E1200), natural extracts (e.g., quillaia (E999), and the like.
In some embodiments, the active agent layer 16a may include a plasticizer. The term “plasticizer” or “softener” typically refers to a substance, compound, or mixture that is added to increase the flexibility of the thickening agent. Suitable plasticizers include polyglycols polyglycerols, polyols, polyethylene glycols (PEG, polyethylene glycols (e.g., PEG-200, PEG-300, PEG-400, PEG-4000, PEG-6000), di(2-ethylhexyl)phthalate (DEHP), triethylene glycol, and the like.
In some embodiments, combining a one or more organic components with an active agent may promote or enhance absorption of the active agent into the skin. For example, surfactants may alter protein structure or fluidize skin and increase permeation. In some embodiments, absorption of ionic or polar active agents may be enhanced by including surfactants with hydrophilic head groups. A lipophilic portion of the surfactant may assist the permeation through skin.
Optionally, the active agent layer may include additional agents such as analgesics, anesthetics, anesthetics vaccines, antibiotics, adjuvants, immunological adjuvants, immunogens, tolerogens, allergens, toll-like receptor agonists, toll-like receptor antagonists, immuno-adjuvants, immuno-modulators, immuno-response agents, immuno-stimulators, specific immuno-stimulators, non-specific immuno-stimulators, and immuno-suppressants, or combinations thereof.
In certain embodiments, the active agent layer is substantially anhydrous and oil-free. It is considered “substantially anhydrous” when the active agent layer contains no more than 5% by weight of water, and more typically, no more than 3%, 2%, 1% or 0.5% of water. Under the substantially anhydrous condition, the ionizable active agent remains electrical neutral, which is generally more stable than its ionized form. Thus, longer shelf-life of the active agent can be expected. It is consider “substantially oil-free” when the active agent layer contains no more than 5% by weight of a lipophilic component such as fatty acids, vegetable oil, petroleum or mineral oil, including short chain (e.g., fewer than 14 carbons) saturated hydrocarbons, silicone oils and the like. These conventional permeation enhancers are not necessary to provide assistance to ionic permeation. On the other hand, because oil tends to destabilize the ionizable or ionized active agent during storage or delivery, an oil-free active agent layer is expected to provide long-term stability to the active agent.
In various embodiments, the amount of ionizable active agent in the active agent layer depends on both its permeation rate and dosage regimen. In addition, the concentration of the ionizable active agent in the active agent layer 16a is selected dependent on factors such as, but not limited to, the solubility of the ionized active agent, the rate of solution of the ionizable active agent, and so forth.
The initial loading of the ionizable active agent also influences the permeation of the ionized active agent. Higher concentration of the ionizable active agent can lead to higher permeation rate. Thus, it is desirable to load maximum amount of the active agent within a minimum amount of the thickening agent (i.e., forming the highest concentration of active agent in a thinnest active agent layer). On the other hand, because the active agent is not typically fully absorbed by the skin, care should be taken to limit the initial loading level to ensure that even at a full dose, the patch is not lethal if ingested. For example, a Procaterol HCl patch typically contains about 25 μg to maximally 100 μg Procaterol HCl.
Typically, the active agent layer may include from about 0.001 wt % to about 10 wt % of an ionizable active agent, more typically, the active agent layer may include from about 0.01 wt % to 5 wt %, or from about 0.01 wt % to 0.1 wt %, 0.1 wt % to 1 wt %, 0.1 wt % to 5 wt % of the an ionizable active agent.
In certain embodiments, the active agent layer comprises HPC and Procaterol HCl. In a more specific embodiment, the active agent layer comprises HPC, Procaterol HCl and urea. In other embodiments, the active agent layer comprises HPC, Procaterol HCl, and glycerol. In other embodiments, the active agent layer comprises HPC, Lidocaine HCl, and glycerol. In other embodiments, the active agent layer comprises HPC and Sodium Diclofenc. In other embodiments, the active agent layer comprises HPC and AA2-G.
In other embodiments, the active agent layer consists essentially of a thickening agent, an ionizable active agent and a humectant. In a particular embodiment, the active agent layer consists essentially of HPC, Procaterol HCl and urea.
As discussed, a variety of ionizable active agents are capable of dissociating into ions that transport through the skin. When analyzing the transdermal delivery of an ionic substance into the skin, simple diffusion based upon a concentration gradient cannot provide a complete picture of the events that take place. Without being bound by the following theories, an analysis is provided herein to explain the ionic transdermal mechanism based on electric potential in addition to concentration gradients. It is believed that the driving force for ion transport through a membrane (e.g., skin) relates to both concentration gradients and electric potential gradients induced by the ionic flux. As used herein, “flux” or “ionic flux” refers to the rate of an ionic substance (i.e., ionized active agent) that moves across a unit area. Typically, ionic flux is represented by, e.g., μg cm−2·h−1 or mol cm−2·h−1.
Eq. 1 describes a basic ion flux J:
The first term in Eq. 1, often used in analyzing electrochemical systems, relates to ion diffusion while the second term relates to ion movement due to an electric field.
When cations and anions move through the skin, their velocities are defined in Eq. 2.
In Eq. 2, ω+ and ω− represent the molar mobility of cations and anions, respectively, in solution. Cations and anions move independently in solution and in the membrane, but both move according to the same concentration gradient. The relative speeds of anions and cations thus depend only upon Eq. 2. Chemical compounds employed as drugs or cosmetics are often chloride or alkali metal salts of organic substances, meaning that once dissociated into ions, one ion (generally the active agent ion) is much larger than the other. Consequently, the overall size of the drug ion does not change significantly after dissociation, and it is reasonable to expect that the transdermal delivery of the ionic drug due to diffusion (based on concentration gradient) should not differ significantly from that of the neutral molecule.
Eq. 4 shows the relationship between the velocity (v) and flux (J) of the ions. The concentration of the ions (c+ and c−) are identical if the drug being examined consists of monovalent cations and anions, and the velocity of the cation should be the same as that of the anion.
Accordingly, Eq. 5 must be satisfied:
A relationship between the concentration gradient and the electric potential gradient is thus obtained. Integrating Eq. 5 from 0 to d and from c0 to cd leads to an expression showing the electric potential difference (Δφ=dφ/dx) through the membrane.
Thus, substituting Eq. 6 in Eq. 3 gives Eq. 7:
At steady state, it is believed that the ion flux is given by the same equation for anions and cations. Diffusion of both ions occurs depending upon the concentration gradient when a drug permeates as dissociated ions, represented by dc/dx and the diffusion coefficient of Eq. 8.
Further, it is necessary to linearly approximate the concentration gradient or the electric potential gradient to solve equation 9. This leads to equation 10. Integrate equation 10 over C0 to Cd after values for x, 0 to d, and c are obtained. This solves for the flux J, as shown in Eq. 11, which is the so-called Goldman equation.
The potential difference across the skin has been considered for a single component system. In practice, a variety of ionic compounds may be present (including, for example, ionized active agent and ionized additive). Eq. 12 shows a relationship used for multi-component systems.
Thus, a film potential can be calculated provided that the ion mobility (omega) and concentration (c) within the skin are known. The ion transport speed can then be found from the calculated film potential.
As shown above, movement of ions across or within the skin cannot be viewed in a simple diffusion model because the generation of a membrane potential further influences the concentration gradient. It is therefore necessary to experimentally evaluate this phenomenon and effectively use the results in drug product development. It is also desirable to evaluate potential additives based on this theory.
An H-shaped Franz cell (
For anionic active agent, the impacts of the electrical potential difference should be reversed as those of the cationic active agent. Thus, in the condition described in
As shown, the mobility of ions within the skin can be influenced by the components (e.g., ionizable additive) contained in the drug product if those components also permeate into the skin. Enhancers used in the conventional patches can be used to improve the speed of the drug ions as long as the enhancers are not adversely influenced by the electric potential difference. Therefore, enhancers can be effective when used with the products described herein. Further, changes in the flux due to the drug concentration can also be evaluated. The activity coefficient and the osmotic pressure changes depending upon the drug concentration, and this greatly influence the speed of the ionic drug movement.
In addition to creating ions in the aqueous medium, it is also possible to create ionic dissociation in polar matrixes and solvents. For example, emulsion matrixes where water and oil are mixed using a surfactant may also be applied, as well as a variety of polymers having ether or ester bonding, and organic solvents and mixed organic and water solvents having a dielectric constant of 20 or greater.
Specific ionizable active agents are described in more detail below. As shown, these ionizable active agents can be delivered transdermally in an ionized form (upon dissociation in an aqueous medium). In certain embodiments, the transdermal delivery can be assisted in the presence of an ionizable additive.
1. Procaterol HCl
Potentially adverse side effects may occur if more than 100 μg of Procaterol is placed in a transdermal patch and that patch is mistakenly ingested by a user or other individual. Also, medicinal efficacy and safety considerations make it desirable that Procaterol be delivered at a substantially constant rate. Development relating to transdermal delivery patches using Procaterol HCl has been undertaken in the past, but a patch has not yet been developed by others that is able to optimize both factors, including the amount of drug in patch, and rate of delivery. Thus, in various embodiments, the transdermal delivery device comprises Procaterol HCl in the active agent layer, wherein at least 50%, or at least 60%, or at least 75% or at least 90% of an initial amount (loading) of Procaterol HCl is delivered over a period of 24 hours. Typically, for safety concerns, the remaining Procaterol HCl after delivery should not exceed 50% of the initial loading of Procaterol HCl.
To load Procaterol HCl on a transdermal delivery device (e.g., a patch), an aqueous solution of Procaterol, or more preferably, a viscous sol using hydroxypropyl cellulose (HPC) can be applied on top of a polyethylene terephthalate (PET) film. Typically, no more than 100 micrograms of Procaterol can be loaded. The patch can be dried to remove any water present during the loading process.
The mobility of the Procaterol cations with respect to the mobility of chloride ions can be obtained based on the results of the membrane electrical potential measurement. It is noted that the mobilities of Na+ and Cl− are nearly the same, as seen from results of measuring the membrane potential using sodium chloride. Also, The mobility of H+ is on the order of 1500 times higher than the mobility of Cl−, based on the results of measuring the membrane potential using HCl. These values have been used to make calculations. Table 1 shows the results when using 0.12 M Procaterol HCl. Employing values from the Table 1 that are the same as those measured, the ion mobility of Procaterol ions becomes 0.13 with respect to that of chloride ions. It can be seen that the migration speed of Procaterol ions is slow compared to that of chloride ions.
In addition, the flux of Procaterol cations can be computed using these results. Results of the calculations made using Eq. 11 are shown in Table 2.
Further, Table 3 shows experimental results of measurements made using a Franz cell. Skin thickness and chloride ion mobility are necessary to apply Eq. 11, and the chloride ion mobility was assumed to be 1.5×10−13, and the skin thickness was assumed to be 0.01 cm here. The mobility of the chloride ion is on the order of 1/10,000 of that found in an aqueous solution. However, this assumption is thought to be reasonable considering the results for solid polymer electrolytes.
Table 3 shows the actual amount of aqueous Procaterol delivered to hairless mouse skin over time was measured using the Franz cell of
2. Sodium Diclofenac
High concentrations of sodium Diclofenac do not easily dissolve in water, and it is thus customary to use a hydrophobic solvent. However, many hydrophobic solvents are irritating to the skin, and therefore cannot readily be used for a patch medication.
In certain embodiments, a transdermal delivery device including sodium Diclofenac and an ionizable additive is capable of delivering therapeutically effective amount of Diclofenac in an aqueous condition (e.g., upon contacting skin and sweat on the skin). Sodium Diclofenac dissociates into Diclofenac anions and sodium cations. The mobility of Diclofenac anions was found by performing measurements of the membrane potential of the skin.
The mobility of Diclofenac anions was found to be 4.6 (compared to that of chloride ions). This means that Diclofenac anions can be more easily delivered to the skin than chloride ions. Further, computational results shown in Table 5 can be obtained for the Diclofenac flux.
Table 6 shows measured results.
The membrane potential shows negative values. Anions thus pass into the skin while undergoing a deceleration. It follows that, by reducing the potential difference occurring within the skin to zero, or making it positive, it is possible to improve the delivery rate. One possible method considered is to use KCl as an additive. KCl dissociates into K+ and Cl− ions. From separate membrane potential measurements, the mobility of K+ within the skin was found to be large compared to that of Cl−. It is thus thought that KCl could be used to lower the negative electric potential gradient occurring within the skin. 0.1% and 0.5% KCl was added to the Diclofenac solution and measurements of membrane potential were performed, the results of which are shown in Table 7.
The membrane potential difference indeed became smaller upon addition of the KCl additive, which reduced the electric potential gradient that tends to hinder delivery of Diclofenac into the skin. It can be seen that the amount that the electric potential gradient is reduced depends upon the amount of KCl added. In addition, it can also be seen that a much greater flux was obtained with the sodium Diclofenac solution containing the KCl additive compared to the solution without KCl. The delivery rate of Diclofenac can thus be controlled by selecting an appropriate additive to reduce the electric potential difference occurring within the skin.
Diclofenac and 0.1% KCl can be used to manufacture a transdermal patch by employing a sol similar to that used for Procaterol. Table 8 shows a comparison to three Diclofenac products currently on the market. Our patch shows higher delivery.
Thus, a specific embodiment provides a transdermal delivery device including in an active agent layer, Diclofenac and 0.1% KCl, and a sol similar to that used for Procaterol. Table 8 shows a comparison to three Diclofenac products currently on the market. The patch (F26) containing ionizable additive KCl shows higher delivery.
3. Ascorbic Acid and Derivatives Thereof
Ascorbic acid is a two-glucoside conductor with high water solubility. Hydrophobic ascorbic acid derivatives have been developed in order to increase the skin permeation of ascorbic acid. However, hydrophobic ascorbic acid derivatives may be combined with a hydrophobic base in which a variety of additives may be used. This may lead to skin irritation, and patches using such formulations may not be well accepted by the public. It is thus described herein a topical formulation (e.g., a hydrophilic lotion) having superior usability, without irritation, without the use of additives by using ascorbic acid 2-glucoside.
Ascorbic acid 2-glucoside (AA2G) dissociates into AA2G− and H+ ions.
It is possible to find the mobility of AA2G− (compared to that of chloride ions) from the film potential, and Table 9 shows results for AA2G at 0.3 M. From this table, the ratio between the mobility of AA2G− and chloride ions is 0.83.
The flux of AA2G− can then be computed using these results. Table 10 shows results when Eq. 11 is used.
Table 11 shows experimental results for flux measurement. A comparison between the computational results and the experimental results is shown in
4. Lidocaine HCl
Due to the low permeation rate of Lidocaine, is necessary to employ a high concentration of Lidocaine HCl in order to achieve an anesthetic effect. High concentrations of Lidocaine HCl, however, are irritating to the skin. It is thus desirable to develop a patch capable of exhibiting a sufficient anesthetizing effect by effectively delivering Lidocaine into the skin. More specifically, concentrations of Lidocaine HCl that are favorable for permeation can be established according the theoretical model described herein.
Lidocaine HCl dissociates into Lidocaine cations (protonated Lidocaine) and Cl− ions in water. A relationship between the concentration of Lidocaine HCl and Lidocaine cations delivered within the skin is shown in
The mobility of Lidocaine cations with respect to chloride ions can be found from the membrane potential results. Results for 5% Lidocaine (185 mM) are shown in Table 12. Using a value from the table where the membrane potential is the same as actual measurements, the mobility of Lidocaine cations is 0.67 that of chloride ions. Lidocaine cations move relatively slower than chloride ions.
Results of computing Lidocaine cation flux are shown in Table 13, while experimental results are shown in Table 14.
Calculations were made assuming a skin thickness of 0.01 cm and a chloride ion mobility of 1.5×10−13.
In certain embodiments, the active agent layer described in connection with the transdermal delivery device can be hydrated to form topical formulations. The topically formulation can be applied directly and freely to the skin of a subject. Thus, certain embodiments provide a topical formulation including a thickening agent and an ionized active agent, as described herein, in combination with an aqueous medium, wherein the topical formulation is substantially oil-free. The topical formulations are typically formulated into spreadable forms (e.g., plasters and paste) according to known methods in the art. Various additives, including permeation enhancers, antioxidants can be further combined with the topical formulation.
In certain embodiments, the ionized active agent can be based on any of the ionizable active agents described herein. One specific embodiment provides a topical formulation comprising Procaterol cation (e.g., Procaterol HCl). For example, the topical formulation includes HPC, Procaterol, urea, and water to provide an aqueous-based formulation. Another specific embodiment provides a topical formulation comprising Lidocaine cations (e.g., Lidocaine HCl). A further specific embodiment provides a topical formulation comprising AA2G anion. A further specific embodiment provides a topical formulation comprising Diclofenac anion (e.g., sodium Diclofenac). As in the passive patch application, ionized additives can be added to adjust the electrical potential difference. Advantageously, the absence of oil in the topical formulation promotes long-term stability of the ionized active agent in the topical formulation.
The topical formulation can be formulated and used according to known methods in the art.
The transdermal delivery device and topical formulations described herein can be constructed by known methods in the art.
Typically, an active agent layer can be prepared by dispersing an ionizable active agent in a viscous sol based on a thickening agent (e.g., HPC). This was applied on top of a backing substrate, e.g., polyethylene terephthalate (PET) film. The backing substrate can be in the shape of a patch, tape, disc, and so forth.
At 402, a backing substrate 12 is provided. The backing substrate 12 has a first surface 13 and an opposed second surface 125.
At 404, a base layer 14 having a thermoplastic resin is formed on the first surface 13 of the backing substrate 12. In some embodiments, the base layer 16 includes a poly(ethylene terephthalate) material
At 406, an active agent layer 16 is formed on the base layer 14 on the first surface 13 of the backing substrate 12. The active agent layer 16 may include a thickening agent, a humectant, and a therapeutically effective amount of a β2-adrenoreceptor agonist (or β2-adrenoreceptor stimulant) or derivative or pharmaceutically acceptable salt thereof.
In some embodiments, forming an active agent layer 16 on the base layer 14 on the first surface of the backing substrate 12 includes spin-coating a composition thereon. Compositions that may be spin-coated include, but are not limited to: a composition having a thickening agent, a humectant, and a therapeutically effective amount of an ionizable active agent. For example, the active agent layer may comprise hydroxypropyl cellulose, glycerol or urea, and Procaterol HCl or other β2-adrenoreceptor agonist in various amounts such as an amount ranging from about 0.1 wt % to about 5 wt % of the total composition.
At 408, which in some embodiments is optional, an active agent replenishing layer 18 adjacent to the active agent layer 16 is formed. The active agent replenishing layer 18 may be spin coated onto the active agent layer and may include an ion exchange material and a sufficient amount of the ionizable active agent (e.g., β2-adrenoreceptor agonist) to maintain a weight percent composition of about 0.1 wt % to about 5 wt % in the active agent layer 16.
In
In
Sol structures can be investigated by dynamic light scattering (DLS). Scattered laser light can be used to identify the state of the HPC contained in the sol.
The aggregate state between HPC and Procaterol becomes an important factor in regulating the active agent sol in the patch. Procaterol HCl is cationic, and HPC is highly hydrophilic. HPC may also be considered to have anionic properties when its pH is acidic, thus leading to the development of aggregates.
For a topical formulation, the ionizable active agent (e.g., AA2G) can be formulated into lotions, cream, emulsions according to known methods in the art.
The ionizable active agent described herein can thus be delivered transdermally in a therapeutically effective amount for treatment of various conditions. Certain embodiments describe method of treating a condition associated with an obstructive respiratory ailment by applying a transdermal delivery device to the skin of a subject, the transdermal delivery device including an active agent layer comprising a β-adrenoreceptor stimulant such as Procaterol HCl.
Obstructive respiratory ailments including, for example, asthma (e.g., allergic asthma, bronchial asthma, and intrinsic asthma), bronchoconstrictive disorders, chronic obstructive pulmonary disease, and the like, affect millions of children and adults worldwide. These ailments are typically characterized by bronchial hyper-responsiveness, inflammation (e.g., airway inflammation), increased mucus production, and/or intermittent airway obstruction, often in response to one or more triggers or stresses. For example, obstructive respiratory ailments may result from exposure to an environmental stimulant or allergen, air pollutants, cold air, exercise or exertion, emotional stress, and the like. In children, the most common triggers are viral illnesses such as those that cause the common cold. Signs of an asthmatic episode include wheezing, shortness of breath, chest tightness, coughing, rapid breathing (tachypnea), prolonged expiration, a rapid heart rate (tachycardia), rhonchous lung sounds, over-inflation of the chest, and the like.
Ionizable active agents belong to the class of amine-containing β-adrenoreceptor stimulants can be formulated into an active agent layer and delivered transdermally into a subject according to various embodiments. β2-receptors are generally located on a number of tissues including blood vessels, bronchi, gastro intestinal tract, skeletal muscle, liver, and mast cell. Typically β2-adrenoreceptor agonist act on the β2-adrenergic receptor eliciting smooth muscle relaxation resulting in dilation of bronchial passages (bronchodilation), relaxation of the gastro intestinal tract, vasodilation in muscle and liver, relaxation of uterine muscle and release of insulin, glycogenolysis in the liver, tremor in skeletal muscle, inhibition of histamine release from mast cells, and the like. β2-adrenoreceptor agonists are useful for treating asthma and other related bronchospastic conditions, and the like. β-receptor antagonists are also useful as anti-hypertensive agents.
Thus, one embodiment provides a method for treating a condition associated with an obstructive respiratory ailment in a subject comprising: applying to the subject's skin a passive transdermal delivery device comprising: a backing substrate; and an active agent layer, wherein the active agent layer is substantially anhydrous and oil-free and includes a thickening agent and an ionizable active agent, and wherein the ionizable active agent is electrically neutral in the active agent layer and dissociates into an ionized active agent upon contacting an aqueous medium; and allowing the ionizable active agent to dissociate into the ionized active agent.
In certain embodiments, the method comprises contacting the ionizable active agent to sweat of the subject's skin to produce the ionized active agent.
In other embodiments, the ionizable active agent is a β-receptor antagonist. In a specific embodiment, the ionizable active agent is Procaterol HCl.
In some embodiments, at least 50% of the Procaterol HCl is delivered through the skin of the subject within a 24 hour period.
At 660, a transdermal delivery device comprising from about 25 μg to about 100 μg of an active agent having β-adrenoreceptor stimulant activity is applied to a biological interface of a subject. A skill artisan can select an appropriate amount of an active agent, however, based on the condition to be treated or the pharmacokinetics, or other criteria or properties of the active agent to achieve the desired effect (e.g., an amount sufficient to alleviate the condition associated with an obstructive respiratory ailment).
At 670, the active agent having β-adrenoreceptor stimulant activity is delivered to the biological interface in an amount sufficient to alleviate the condition associated with an obstructive respiratory ailment.
In some embodiments, transdermally delivering the active agent having β-adrenoreceptor stimulant activity to the biological interface includes transferring a therapeutically effective amount of a β2-adrenoreceptor agonist to the biological interface of the subjected via diffusion. In some embodiments, transdermally delivering the active agent having β-adrenoreceptor stimulant activity to the biological interface includes transferring a therapeutically effective amount of a β2-adrenoreceptor agonist selected from Procaterol HCl, Procaterol HCl hemihydrate, or a derivative or pharmaceutically acceptable salt thereof to the biological interface of the subjected.
In the description above, active agents such as ionic exchange materials were described as being disposed on a patch for being applied to the skin of a subject. In alternative embodiments, active agents including, but not limited to, ion exchange materials may be in the form of a powder or cream that may be applied to the skin of a subject.
The various embodiments described herein are further illustrated by the following non-limiting examples.
1. In-Vitro Permeation Testing
Delivery devices 10a, 10b, and 10c, which are hereinafter collectively referred to as delivery device 10, may be tested using both in vitro and in vivo. In vitro testing may be performed using a passive diffusion-testing device such as a Kelder cell or a Franz cell, among other types of testing devices.
The passive diffusion measuring device 750 includes a first end plate 752 and a second end plate 754. A plurality of coupling features such as holes 756 are formed on the first end plate 752. The second end plate 754 includes a number of coupling features such as arms 758, which are complementarily aligned with the holes 756. The holes 756 are sized and shaped to receive at least a portion of the arms 758. In operable position, a portion of the arms 758 extend through the holes 756, and the arms 758 receive fasteners 760, which hold the arms in place.
Sandwiched between the first end plate 752 and the second end plate 754 is a first cap 762, the delivery device 10, a permeable membrane 764, a reservoir 766, and a second cap 768. The first cap 762 abuts the first end plate 752, and the second cap 768 abuts the second end plate 754. The first cap 762 and the second cap 768 may be non-permeable and made from a material such as silicon rubber.
The delivery device 10 interposes first cap 762 and the permeable membrane 764. In the experiments described below, the permeable membrane 764 is a piece of human skin or animal skin (e.g., hairless mouse skin obtained from “HOS hr-1” male mice).
Interposing the permeable membrane 764 and the second cap 768 is the reservoir 766. The reservoir 766 is made from a non-permeable material such as rubber, silicon rubber, glass, and the like. The reservoir 766 may be generally cylindrical with an open end 770 that is in fluidic communication with a generally hollow interior 772. The open end 770 abuts the permeable membrane 764. A fluid 774 such as Phosphate Buffered Saline (PBS) is disposed in the hollow interior 772. At the open end 770, the fluid 774 contacts the permeable membrane 764. The active agent in the delivery device diffuses through the permeable membrane 764 in to the fluid 774. In the experiments described below, the reservoir 766 may hold about 4 milliliters of the fluid 774.
2. In-Vitro Testing Conditions and Measurements
Typically, 17 ml of phosphate buffered saline (PBS, sold by Wako Pure Chemical Industries) was injected into the receptor cell, and a 10 mm stirring bar was used to agitate the solution during the test. The Franz cell was placed in an incubator (made by ESPEC, model LH-113) with the temperature set to 32° C. and the humidity set to 70%. Samples were typically extracted from the cell at predetermined times using a 200 μl Gilson Pipetman. 200 μl of PBS was then added to the cell after each sampling operation.
For measuring the active agent (e.g., Procaterol cation) permeated, a standard solution with known concentration can be prepared and compared with the concentration measured. Using Procaterol HCl as an example, 50 mg of Procaterol HCl (97.25% anhydrous) was accurately measured out, and then added to water to form 50 ml of solution (“Procaterol concentrate liquid”). The standard concentrate was then diluted (“Procaterol standard solution”) and used as a mobile phase for high performance (or pressure) liquid chromatography (HPLC). The Procaterol concentrate liquid was sealed in a light shielding bottle and stored in a refrigerator. 10 μl of each test sample and 10 μl of the standard solution was measured using HPLC, and Procaterol peak areas At (test samples) and As (standard solution) were determined for each sample. Procaterol HCl masses were then found for each test sample using the following equation:
Amount of Procaterol HCl in test solution (g/μl)=amount of anhydrous Procaterol in standard concentrate liquid×At/As×1.0276, where 1.0276 is the ratio between the molecular weight of ½ hydrated Procaterol HCl/the molecular weight of anhydrous Procaterol HCl=335.83/326.82
Below are an exemplary condition and instrument for measuring the concentration of Procaterol cations permeated:
Model: Shimazu HPLC LC-2010A HT
Column: Shinwa Chemical Industries, Ltd.
model STRUCTURE ODS-II
150 mm length×4.6 mm internal diameter
Temperature: 40° C.
Mobile phase: 5 m-mol dm−3 of a mixture of pentane sulfonic acid/methanol/acetic acid (76:23:1)
Flow rate: 1 ml min−1
Amount injected: 10 μl
Unless indicated otherwise, hairless mouse skin obtained from “HOS: hr-1”, 5 weeks old male mice:
Set up glass chambers to run at 32.5° C.
Approximately 3.4 ml of DPBS in chamber
Chambers 1, 2, 3, 4, 5 TT spincoat
Chambers 6, 7 PP-HPC
Chambers 8, 9 PET-HPC
3. Exemplary Patch Preparations
Preparation 1: 23.5 μg Procaterol patch (1.13 cm2) was made by spin-coating an active agent layer 16 composition comprising 2.5 wt % Procaterol-Hydrochloride (HCl), 0.5 wt % HPC in a 10 wt % Glycerol solution on to a 12 mm diameter PET base layer 16 on a backing sheet (3M).
Preparation 2: 2.5 mg Procaterol patches were made by adding 100 μL of a 25 mg/ml Procaterol/10 wt % glycerol solution/ to a 10 mm diameter single PET-Klucel layer disc.
Preparation 3: 0.75 mg Procaterol patches were made by adding 30 μL of a 25 mg/ml Procaterol/10 wt % glycerol solution/ to a 12 mm diameter two PP-Klucel layer disc.
In Example 1, before testing the delivery device 10, sixteen tests were performed at four different agent concentrations (four tests (#1, #2, #3, and #4) for each concentration of active agent) using Procaterol HCl in order to investigate the transport of Procaterol cation into and through skin along a concentration gradient. A Franz cell was used at 32° C. using hairless mouse skin as a permeable membrane. 720 corresponds to the average delivery of a 5 wt % Procaterol-HCl concentration, 722 corresponds to the average delivery of a 2.5 wt % Procaterol-HCl concentration, 724 corresponds to the average delivery of a 1 wt % Procaterol-HCl concentration, and 726 corresponds to the average delivery of a 0.5 wt % Procaterol-HCl concentration.
It is generally possible to manufacture a transdermal delivery patch using a hydrophilic gel polymer matrix such as polyvinyl pyrrolidone or polyvinyl alcohol. Procaterol is a hydrophilic active agent, however, and thus smooth release from within a polymer matrix may not always be possible.
Examples 2-7 described below generally employed a high viscosity sol solution in order to hold Procaterol. Several wt % of hydroxypropyl cellulose (HPC) was dissolved in water in order to form an active agent containing sol. Procaterol HCl was then dissolved in the sol. The sol was applied to a PET sheet, forming a patch. Glycerol (generally 10 wt %) was added to, among other things, promote delivery. The amount of active agent solution applied to the PET contained approximately 20 μg/cm2 of Procaterol. In some tests, a composition of HPC and glycerol was made and allowed to repose for a given period of time, such as a day or two. In some situations, the period of repose may be shorter or longer.
Patches were applied to the skin (frozen or raw) of a hairless mouse, and the amount of Procaterol delivered was measured using the previously described Frantz cell setup, with the patch replacing the solution. Experiments 2-7 show that the amount of Procaterol on the donor side increases over time, and passes through the skin. Although Examples 2-7 can measure the amount of Procaterol delivered through the skin, the actual delivery mechanism of Procaterol may be complex.
One lot of six delivery devices was prepared according to the embodiment shown in
In Example 3, one lot of eight delivery devices was prepared according to the embodiment shown in
In Example 4, one lot of ten delivery devices was prepared according to the embodiment shown in
In Example 5, eighteen delivery devices were prepared according to the embodiment shown in
In Example 6, fourteen delivery devices were prepared according to the embodiment shown in
In Example 7, eight delivery devices were prepared according to the embodiment shown in
This application claims the benefit under 35 U.S.C. § 119(e) of U.S. Provisional Patent Application No. 60/938,961 filed May 18, 2007; U.S. Provisional Patent Application No. 60/955,850 filed Aug. 14, 2007; U.S. Provisional Patent Application No. 60/956,895 filed Aug. 20, 2007; and U.S. Provisional Patent Application No. 60/957,126 filed Aug. 21, 2007.
| Number | Date | Country | |
|---|---|---|---|
| 60957126 | Aug 2007 | US | |
| 60956895 | Aug 2007 | US | |
| 60955850 | Aug 2007 | US | |
| 60938961 | May 2007 | US |
