Patent Application
20240277606
Delivery devices capable of delivering bioactive agents over several months is an attractive approach for treating certain types of disease states. For example, depression is a major public health burden domestically and worldwide. Treatment options for patients with major depressive disorder (MDD) consist primarily of psychotherapy and pharmacotherapy. In the latter category specifically, there have been only incremental advances in treatment options until recently when Esketamine, a form of ketamine given as a nasal spray, was approved.
Primary challenges to the treatment of MDD are the relatively low response rates to medication as well as high relapse in a large subset of patients. The most comprehensive study of MDD undertaken was the National Institute of Mental Health-funded Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial. The trial outlined an algorithmic, sequential treatment approach and thus allows for an estimated likelihood of antidepressant success with subsequent trials. Acute remission rates declined with each additional trial (trial 1, 37%; trial 2, 31%; trial 3, 14%; trial 4, 13%). Correspondingly, the probabilities of remitting and maintaining remission for 1 year decrease with each additional trial (26% for level 1, 14% for level 2, 5% for level 3, and 3% for level 4). Unfortunately, this corresponds to over 43% of patients who fail the first two trials.
Microdosing is one approach for the treatment of depression and other diseases; however, there are limitations to this approach. For example, a major hurdle to furthering the research on 5HT2A agonists such as LSD and psilocybin for the treatment of depression is their current status as Schedule I drugs. Given the potential concerns around diversion or abuse of these compounds, as well as the strict controls on their distribution, dosing is limited to monitored settings. This requires patients to come in for dosing on an every-other (Q48) or every-third day (Q72) schedule for several weeks, which will likely limit patient participation and treatment. Thus, what is needed is the pulsed delivery of bioactive agents to patients such that the patient does not need to be responsible for taking the bioactive agent but is delivered automatically upon administration to the patient.
Described herein are methods for providing the pulsed delivery of a bioactive agent, such as a 5HT2A agonist, to a subject upon administration of a device to the subject. The device is composed of biodegradable polymers such that when administered to the subject the polymers on the surface of the device erode and release the bioactive agent. In one aspect, the device is composed of alternating layers of biodegradable polymers, where every other layer includes the bioactive agent. In a further aspect, one or more of the layers can be composed of a mixture of cellulose acetate phthalate (CAP) and a poloxamer. The layers that do not include the bioactive agent functions as “blanks,” which can be used to control the release rate of the bioactive agent. In a still further aspect, one or more sides of the device can be coated with a biodegradable and/or biocompatible polymer such that the bioactive agent is released from only one side of the device.
Other systems, methods, features, and advantages of the present disclosure will be or become apparent to one with skill in the art upon examination of the following drawings and detailed description. It is intended that all such additional systems, methods, features, and advantages be included within this description, be within the scope of the present disclosure, and be protected by the accompanying claims. In addition, all optional and preferred features and modifications of the described embodiments are usable in all aspects of the disclosure taught herein. Furthermore, the individual features of the dependent claims, as well as all optional and preferred features and modifications of the described embodiments are combinable and interchangeable with one another.
Many aspects of the present disclosure can be better understood with reference to the following drawings. The components in the drawings are not necessarily to scale, emphasis instead being placed upon clearly illustrating the principles of the present disclosure. Moreover, in the drawings, like reference numerals designate corresponding parts throughout the several views.
Additional advantages of the invention will be set forth in part in the description which follows, and in part will be obvious from the description, or can be learned by practice of the invention. The advantages of the invention will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims. It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention, as claimed.
In one aspect, disclosed herein is a method for the pulsed delivery of a 5HT2A agonist to a subject, the method including at least the steps of administering to the subject a device composed of a layer structure including:
In some aspects, additional pairs of layers are also included, such that stacks of layers are formed wherein layers containing 5HT2A agonists alternate with layers that do not include 5HT2A agonists. Many modifications and other embodiments disclosed herein will come to mind to one skilled in the art to which the disclosed compositions and methods pertain having the benefit of the teachings presented in the foregoing descriptions and the associated drawings. Therefore, it is to be understood that the disclosures are not to be limited to the specific embodiments disclosed and that modifications and other embodiments are intended to be included within the scope of the appended claims. The skilled artisan will recognize many variants and adaptations of the aspects described herein. These variants and adaptations are intended to be included in the teachings of this disclosure and to be encompassed by the claims herein.
Although specific terms are employed herein, they are used in a generic and descriptive sense only and not for purposes of limitation.
As will be apparent to those of skill in the art upon reading this disclosure, each of the individual embodiments described and illustrated herein has discrete components and features which may be readily separated from or combined with the features of any of the other several embodiments without departing from the scope or spirit of the present disclosure.
Any recited method can be carried out in the order of events recited or in any other order that is logically possible. That is, unless otherwise expressly stated, it is in no way intended that any method or aspect set forth herein be construed as requiring that its steps be performed in a specific order. Accordingly, where a method claim does not specifically state in the claims or descriptions that the steps are to be limited to a specific order, it is no way intended that an order be inferred, in any respect. This holds for any possible non-express basis for interpretation, including matters of logic with respect to arrangement of steps or operational flow, plain meaning derived from grammatical organization or punctuation, or the number or type of aspects described in the specification.
All publications mentioned herein are incorporated herein by reference to disclose and describe the methods and/or materials in connection with which the publications are cited. The publications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention. Further, the dates of publication provided herein can be different from the actual publication dates, which can require independent confirmation.
While aspects of the present disclosure can be described and claimed in a particular statutory class, such as the system statutory class, this is for convenience only and one of skill in the art will understand that each aspect of the present disclosure can be described and claimed in any statutory class.
It is also to be understood that the terminology used herein is for the purpose of describing particular aspects only and is not intended to be limiting. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the disclosed compositions and methods belong. It will be further understood that terms, such as those defined in commonly used dictionaries, should be interpreted as having a meaning that is consistent with their meaning in the context of the specification and relevant art and should not be interpreted in an idealized or overly formal sense unless expressly defined herein.
Prior to describing the various aspects of the present disclosure, the following definitions are provided and should be used unless otherwise indicated. Additional terms may be defined elsewhere in the present disclosure.
As used herein, “comprising” is to be interpreted as specifying the presence of the stated features, integers, steps, or components as referred to, but does not preclude the presence or addition of one or more features, integers, steps, or components, or groups thereof. Moreover, each of the terms “by,” “comprising,” “comprises,” “comprised of,” “including,” “includes,” “included,” “involving,” “involves,” “involved,” and “such as” are used in their open, non-limiting sense and may be used interchangeably. Further, the term “comprising” is intended to include examples and aspects encompassed by the terms “consisting essentially of” and “consisting of.” Similarly, the term “consisting essentially of” is intended to include examples encompassed by the term “consisting of.
As used in the specification and the appended claims, the singular forms “a,” “an” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “a bioactive agent” includes, but are not limited to, combinations or mixtures of two or more such bioactive agents, and the like.
It should be noted that ratios, concentrations, amounts, and other numerical data can be expressed herein in a range format. It will be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint. It is also understood that there are a number of values disclosed herein, and that each value is also herein disclosed as “about” that particular value in addition to the value itself. For example, if the value “10” is disclosed, then “about 10” is also disclosed. Ranges can be expressed herein as from “about” one particular value, and/or to “about” another particular value. Similarly, when values are expressed as approximations, by use of the antecedent “about,” it will be understood that the particular value forms a further aspect. For example, if the value “about 10” is disclosed, then “10” is also disclosed.
When a range is expressed, a further aspect includes from the one particular value and/or to the other particular value. For example, where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the disclosure, e.g. the phrase “x to y” includes the range from ‘x’ to ‘y’ as well as the range greater than ‘x’ and less than ‘y.’ The range can also be expressed as an upper limit, e.g. ‘about x, y, z, or less’ and should be interpreted to include the specific ranges of ‘about x,’ ‘about y’, and ‘about z’ as well as the ranges of ‘less than x’, less than y′, and ‘less than z’. Likewise, the phrase ‘about x, y, z, or greater’ should be interpreted to include the specific ranges of ‘about x,’ ‘about y,’ and ‘about z’ as well as the ranges of ‘greater than x,’ greater than y,′ and ‘greater than z.’ In addition, the phrase “about ‘x’ to ‘y’”, where ‘x’ and ‘y’ are numerical values, includes “about ‘x’ to about ‘y’”.
It is to be understood that such a range format is used for convenience and brevity, and thus, should be interpreted in a flexible manner to include not only the numerical values explicitly recited as the limits of the range, but also to include all the individual numerical values or sub-ranges encompassed within that range as if each numerical value and sub-range is explicitly recited. To illustrate, a numerical range of “about 0.1% to 5%” should be interpreted to include not only the explicitly recited values of about 0.1% to about 5%, but also include individual values (e.g., about 1%, about 2%, about 3%, and about 4%) and the sub-ranges (e.g., about 0.5% to about 1.1%; about 5% to about 2.4%; about 0.5% to about 3.2%, and about 0.5% to about 4.4%, and other possible sub-ranges) within the indicated range.
As used herein, the terms “about,” “approximate,” “at or about,” and “substantially” mean that the amount or value in question can be the exact value or a value that provides equivalent results or effects as recited in the claims or taught herein. That is, it is understood that amounts, sizes, formulations, parameters, and other quantities and characteristics are not and need not be exact, but may be approximate and/or larger or smaller, as desired, reflecting tolerances, conversion factors, rounding off, measurement error and the like, and other factors known to those of skill in the art such that equivalent results or effects are obtained. In some circumstances, the value that provides equivalent results or effects cannot be reasonably determined. In such cases, it is generally understood, as used herein, that “about” and “at or about” mean the nominal value indicated±10% variation unless otherwise indicated or inferred. In general, an amount, size, formulation, parameter or other quantity or characteristic is “about,” “approximate,” or “at or about” whether or not expressly stated to be such. It is understood that where “about,” “approximate,” or “at or about” is used before a quantitative value, the parameter also includes the specific quantitative value itself, unless specifically stated otherwise.
As used herein, the terms “optional” or “optionally” means that the subsequently described event or circumstance can or cannot occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.
As used herein, the term “admixing” is defined as mixing two or more components together so that there is no chemical reaction or physical interaction. The term “admixing” also includes the chemical reaction or physical interaction between the two or more components.
As used herein, the terms “treating” and “treatment” can refer generally to obtaining a desired pharmacological and/or physiological effect. The effect can be, but does not necessarily have to be, prophylactic in terms of preventing or partially preventing a disease, symptom, or condition thereof, such as depression, anxiety, obsessive compulsive disorder (OCD), addiction, or any combination thereof. The effect can be therapeutic in terms of a partial or complete cure of a disease, condition, symptom, or adverse effect attributed to the disease, disorder, or condition. The term “treatment” as used herein can include any treatment of depression, anxiety, OCD, addiction, or another neuropsychiatric disease in a subject, particularly a human and can include any one or more of the following: (a) preventing the disease from occurring in a subject which may be predisposed to the disease but has not yet been diagnosed as having it; (b) inhibiting the disease, i.e., arresting its development; and (c) relieving the disease, i.e., mitigating or ameliorating the disease and/or its symptoms or conditions. The term “treatment” as used herein can refer to both therapeutic treatment alone, prophylactic treatment alone, or both therapeutic and prophylactic treatment. Those in need of treatment (subjects in need thereof) can include those already with the disorder and/or those in which the disorder is to be prevented. As used herein, the term “treating”, can include inhibiting the disease, disorder, or condition, e.g., impeding its progress; and relieving the disease, disorder, or condition, e.g., causing regression of the disease, disorder and/or condition. Treating the disease, disorder, or condition can include ameliorating at least one symptom of the particular disease, disorder, or condition, even if the underlying pathophysiology is not affected, e.g., such as treating the pain of a subject by administration of an analgesic agent even though such agent does not treat the cause of the pain.
As used herein, the term “prevent” or “preventing” refers to precluding, averting, obviating, forestalling, stopping, or hindering something from happening, especially by advance action. It is understood that where reduce, inhibit, or prevent are used herein, unless specifically indicated otherwise, the use of the other two words is also expressly disclosed.
Described herein are methods that provide the pulsed delivery of a bioactive agent to a subject upon administration of a device to the subject. The devices are composed of biodegradable polymers such that when administered to the subject the polymers erode and release the bioactive agent at specific time intervals. The term “microdosing” is referred to as the administration of a bioactive agent in small quantities (e.g., microgram scale) every 3-7 days to treat or prevent a disease or symptom thereof.
A delivery device described herein is depicted in
Referring to
In one aspect, when layers 21-25 are composed of the same biodegradable polymer, the second biodegradable polymer includes a mixture of cellulose acetate phthalate (CAP) in the amount of about 50 mol % to about 90 mol % and a poloxamer in the amount of about 10 mol % to about 50 mol %. In another aspect, the second biodegradable polymer includes cellulose acetate phthalate (CAP) in the amount of about 50 mol %, 55 mol %, 60 mol %, 65 mol %, 70 mol %, 75 mol %, 80 mol %, 85 mol %, or 90 mol %, where any value can be a lower and/or upper endpoint of a range (e.g., 60 mol % to 80 mol %, etc.). In another aspect, the second biodegradable polymer includes a poloxamer in the amount of about 10 mol %, 15 mol %, 20 mol %, 25 mol %, 30 mol %, 35 mol %, 40 mol %, 45 mol %, or 50 mol %, where any value can be a lower and/or upper endpoint of a range (e.g., 20 mol % to 40 mol %, etc.).
In one aspect, the poloxamer is a nonionic triblock copolymer composed of a central hydrophobic chain of polyoxypropylene (e.g., (poly(propylene oxide)) flanked by two hydrophilic chains of polyoxyethylene (e.g., poly(ethylene oxide)). In one aspect, poloxamer has the formula
wherein a is from 10 to 100, 20 to 80, 25 to 70, or 25 to 70, or from 50 to 70; b is from 5 to 250, 10 to 225, 20 to 200, 50 to 200, 100 to 200, or 150 to 200. In another aspect, the poloxamer has a molecular weight from 2,000 to 15,000, 3,000 to 14,000, or 4,000 to 12,000. Poloxamers useful herein are sold under the tradename Pluronic® manufactured by BASF. Non-limiting examples of poloxamers useful herein include, but are not limited to, those in Table 1. In one aspect, the poloxamer is F-127.
In one aspect, the poloxamer can have a molecular weight of from about 4 kDa to about 20 kDa, or of about 12.6 kDa, or about 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or about 20 kDa, or a combination of any of the foregoing values, or a range encompassing any of the foregoing values. In another aspect, the poloxamer can have an average ethylene oxide content of from about 10 units to about 300 units, or of about 200.45 units, or of about 10, 50, 100, 150, 200, 250, or about 300 units, or a combination of any of the foregoing values, or a range encompassing any of the foregoing values. In another aspect, the poloxamer can have an ethylene oxide content of from about 25 units to about 100 units, or of about 65.17 units, or of about 25, 50, 75, or about 100 units, or a combination of any of the foregoing values, or a range encompassing any of the foregoing values.
By varying the thickness of the layers, it is possible to control the timing of the release of the bioactive agent from the layered system. In one aspect, the thickness of the second layer 22 and fourth layer 24 is greater than the thickness of the first layer 21, third layer 23, and fifth layer 25. In another aspect, the thickness of the first layer 21, third layer 23, and fifth layer 25 is less than about 0.2 mm, or is from about 0.05 mm to about 0.2 mm, or 0.05 mm, 0.1 mm, 0.15 mm, or 0.2 mm, where any value can be a lower and/or upper endpoint of a range (e.g., 0.05 mm to 1.5 mm, etc.). In one aspect, the first layer, the third layer, and the fifth layer can each independently erode over a period of from about 30 minutes to about 48 hours, or over a period of about 0.5, 1, 2, 3, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, or about 48 hours.
In another aspect, the thickness of the second layer 22 and fourth layer 24 is greater than about 0.3 mm, or is from about 0.2 mm to about 0.5 mm, or 0.2 mm, 0.25 mm, 0.3 mm, 0.35 mm, 0.4 mm, 0.43 mm, or 0.5 mm, where any value can be a lower and/or upper endpoint of a range (e.g., 0.2 mm to 0.4 mm, etc.). In one aspect, the second layer 22 and the fourth layer 24 has a thickness such that the second layer and fourth layer each independently erode over a period of about 48 hours to about 96 hours, or about 72 hours.
The layered system as depicted in
After the layered system has been prepared, the system is coated on three sides with a biocompatible and slowly-degrading bioresorbable polymer (26 as depicted in
In some aspects, the layered system further includes a seventh layer situated between the fifth layer and the sixth biodegradable/bioresorbable polymer, wherein the seventh layer includes a seventh biodegradable polymer. In some aspects, the seventh biodegradable polymer can be the same polymer as the second and fourth biodegradable polymers, or can be different from the second and fourth biodegradable polymers. In any of these aspects, the seventh layer can cover one surface of the fifth layer so that degradation or erosion of the fifth layer can happen from only one side, thereby ensuring release of any active compounds from the fifth layer at the same rate as release from the first and third layers.
In some aspects, the second, fourth, and/or seventh layer (if present) can further be subdivided into sub-layers. In one aspect, the second layer can include a first sub-layer and a second sub-layer, wherein each of the first and second sub-layers can comprise the second biodegradable polymer. In another aspect, the first and second sub-layers can each independently be about 0.4 mm thick.
In another aspect, the fourth layer can include a third sub-layer and a fourth sub-layer, wherein each of the third and fourth sub-layers can comprise the fourth biodegradable polymer. In another aspect, the third and fourth sub-layers can each independently be about 0.4 mm thick.
In still another aspect, the seventh layer can include a fifth sub-layer and a sixth sub-layer, wherein each of the fifth and sixth sub-layers can comprise the seventh biodegradable polymer. In another aspect, the fifth and sixth sub-layers can each independently be about 0.4 mm thick.
In any of these aspects, the device used in the disclosed methods can be a film having a thickness of from about 0.05 mm to about 2 mm, or of about 0.05, 0.1, 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, or about 2 mm, or a combination of any of the foregoing values, or a range encompassing any of the foregoing values. In some aspects, the sixth layer or coating can be added to the thickness of the film such that the sixth layer or coating increases the thickness of the film by an amount equal to the thickness of the sixth layer or coating (e.g. a 1 mm film with a 2 mm coating can have a total thickness of 3 mm, and the like).
The devices described herein and the methods for producing the same permit the inclusion of a variety of different types of bioactive agents. In one aspect, the bioactive agent includes an antibiotic, a pain reliever, an immune modulator, a growth factor, an enzyme inhibitor, a hormone, a messenger molecule, a cell signaling molecule, a receptor agonist, an oncolytic virus, a chemotherapy agent, a receptor antagonist, a nucleic acid, or any combination thereof.
In another aspect, the bioactive agent includes a 5HT2A agonist such as, for example, 2,5-dimethoxy-4-iodoamphetamine (DOI), 1-acetyl-N,N-diethyllysergamide (ALD-52), O-acetylpsilocin (4-AcO-DMT), lysergic acid diethylamide (LSD), N1-(cyclopropylmethanoyl)-lysergic acid diethylamide (1CP-LSD), or psilocybin. The devices as described herein are capable of delivering consistent, long-term microdoses of the 5HT2A agonist that will overcome major barriers of compliance, cost, and abuse. The microfuse devices described herein are an efficacious and safe way to perform microdosing by delivering the bioactive agent about every 48 hours to about 96 hours, or about 72 hours over many months.
The devices described herein can be administered to a subject using techniques known in the art. In one aspect, the device is implanted in the subject. In one aspect, a clinician can subcutaneously inject the device instead of performing a minor surgical procedure. This streamlined implantation procedure will save time and money and increase patient compliance even further. In another aspect, the devices described herein can be formulated with a pharmaceutically-acceptable excipient suitable for injection. In any of these aspects, the subject can be in need of treatment or prevention of depression, anxiety, obsessive compulsive disorder (OCD), or addiction.
Now having described the aspects of the present disclosure, in general, the following Examples describe some additional aspects of the present disclosure. While aspects of the present disclosure are described in connection with the following examples and the corresponding text and figures, there is no intent to limit aspects of the present disclosure to this description. On the contrary, the intent is to cover all alternatives, modifications, and equivalents included within the spirit and scope of the present disclosure.
The present disclosure can be described in accordance with the following numbered aspects, which should not be confused with the claims.
The following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how the compounds, compositions, articles, devices and/or methods claimed herein are made and evaluated, and are intended to be purely exemplary of the disclosure and are not intended to limit the scope of what the inventors regard as their disclosure. Efforts have been made to ensure accuracy with respect to numbers (e.g., amounts, temperature, etc.), but some errors and deviations should be accounted for. Unless indicated otherwise, parts are parts by weight, temperature is in ° C. or is at ambient temperature, and pressure is at or near atmospheric.
The optimum conditions for formation of surface-eroding Cellulose Acetate Phthalate-Pluronic F-127 (CAPP) films of varying thickness was established. After screening a variety of conditions (different mol ratios of CAP to P, solvent choice, evaporation conditions, and polymer weight percent), it was determined that CAP:P mixtures dispersed well at 7% w/v in acetone and 70:30 mol ratio CAP:P films evaporated from acetone at 4° C. to form uniform and rigid films. Using Teflon(PTFE)-coated dishes with uniform diameter, films from 300, 600, 900, and 1200 mg of CAPP polymer mixture were produced. These produced films of ˜0.1, 0.2, 0.3, and 0.4 mm, respectively (
The next goal—knowing the predictable thicknesses of films based on polymer weight—was to establish any correlation between film thickness and erosion time. First, it was confirmed that the CAPP films do degrade via surface erosion, as they maintain similar mechanical properties and decrease in size as degradation occurs. Moreover, erosion time was dependent on the thickness of the films, where 0.1, 0.2, 0.3, and 0.4 mm thick films were fully eroded at 36, 48, 66, and 84 hrs, respectively (
Quantification of Drug Release from Films of Varying Thickness Using Fluorescent Dyes as Drug Surrogates.
Next, drug release from single-layered CAPP films of 0.1, 0.2, 0.3, and 0.4 mm thickness was quantified. Drug release was measured by encapsulating Rhodamine fluorescent dye within the films and closely matched the erosion times reported above. Complete release from 0.1 mm thick films occurred after ˜18 hrs (
Demonstration of Pulsatile Release from Layered Films.
In order to achieve pulsatile release with a Q72 profile, multilayered films were constructed as shown in
We constructed multilayer CAPP films of alternating 0.1 mm bulk eroding, drug-loaded layers and 0.4 mm surface eroding, blank layers and observed drug release kinetics from these films using Rhodamine as a model drug. As shown in
These films can be further optimized to ensure that the maximum concentration of the first peak is more consistent in magnitude with the second and third peaks, and the studies repeated with the 5HT2A agonists DOI, ALD-52, and 4-AcO-DMT. Moreover, the coating that surrounds all but one side of the devices has also been optimized, since the wax and parafilm coating used for in vitro studies are not appropriate for implantation in vivo. The wax/parafilm has been replaced with a coating of the very slowly-degrading biocompatible polymer, poly(sebacic acid).
The protocol for in vitro bioactivity analysis is shown in
“Blank” CAPP films did not show increased calcium flux compared to PBS control, indicating that CAPP films do not agonize the 5HT2A receptor pathway (
Single-layered films loaded with DOI and blank single-layered films have been constructed. These films were sterilized and implanted subcutaneously in the dorsal flap of CD-1 mice in an initial pilot experiment. This pilot experiment enabled optimization of blood collection time points, ensure the ability to detect DOI with current bioanalytical techniques, and will inform the design of the rest of the in vivo studies. The experimental overview of this initial pilot experiment is shown in
Demonstration of Pulsed Delivery of DOI from Multilayer CAPP Films In Vivo
To demonstrate the ability to achieve pulsed delivery of DOI in vivo, multilayered CAPP films were implanted subcutaneously and pharmacokinetics of DOI post-implantation were monitored. The multilayered CAPP films used for this study had seven layers, where layers 1, 4, and 7 were DOI-loaded 0.1 mm thick CAPP films at 70:30 CAP:P ratio and layers 2, 3, 5, and 6 were unloaded (Blank) 0.4 mm thick CAPP films at 90:10 CAP:P ratio. The layered devices were then coated on all sides but one (the top of layer 1) with the biocompatible polymer polysebacic acid (PSA). After implantation, the anticipated pulsed release schedule of DOI was observed, with three distinct DOI pulses where peak concentrations in the plasma occurred at ˜2, 12, and 24 hrs post-implantation. Moreover, the concentration of DOI in the brain, liver, and kidneys matched the pulsed profile of the blood plasma (see
It should be emphasized that the above-described embodiments of the present disclosure are merely possible examples of implementations set forth for a clear understanding of the principles of the disclosure. Many variations and modifications may be made to the above-described embodiment(s) without departing substantially from the spirit and principles of the disclosure. All such modifications and variations are intended to be included herein within the scope of this disclosure and protected by the following claims.
This application claims the benefit of U.S. Provisional Application No. 63/197,632 filed on Jun. 7, 2021, which is incorporated herein by reference in its entirety.
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/US2022/032450 | 6/7/2022 | WO |
| Number | Date | Country | |
|---|---|---|---|
| 63197632 | Jun 2021 | US |
