Implantable devices for drug delivery with reduced burst release

a technology of implantable devices and drug delivery, which is applied in the direction of drug compositions, peptide/protein ingredients, other domestic articles, etc., can solve the problems of impaired cognitive function, inconvenient or difficult compliance with extended dosing regimens, and many problems, so as to improve the control and tuning of the release rate, the effect of reducing the burst releas

Inactive Publication Date: 2021-01-14
FEDSON INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0007]The invention provides implantable drug delivery devices comprising a core comprising a polymer (or polymer blend) and one or more drugs or pharmaceutical substances, and an outer shell comprising a polymer (or polymer blend) and one or more porogen materials. The shell can optionally additionally comprise one or more drugs or pharmaceutical substances. Surrounding the drug-containing core with a porogen-containing shell can reduce the burst release often observed with sustained release formulations. Use of a porogen material having a narrow size distribution, and the resulting narrow size distribution of the pores left in the shell after removal of the porogen, also allows better control and tuning of the release rate of the drug from the core.

Problems solved by technology

Several problems can arise during long-term administration of drugs taken orally or by other routes requiring frequent administration.
Compliance with an extended dosing regimen can often be inconvenient or difficult.
For example, patients with impaired cognitive function (due to Alzheimer's disease or other disorders) may not be able to self-administer drugs reliably, requiring a caregiver to ensure that medications are taken properly.
Frequent or periodic administration, such as would occur with daily oral and sublingual delivery, can result in blood concentrations of drug peaking quickly after initial administration, then dropping steeply before the next administration.
One difficulty encountered with virtually all sustained drug formulations, including implants, is burst release.
Burst release is a high release of drug when the formulation is first administered which is higher than the desired release rate, and which can cause deleterious pharmacological effects resulting from excessive levels of drug.
This is particularly undesirable for systems, such as implants, that release thyroid hormones, as dangerous cardiac complications may occur.

Method used

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  • Implantable devices for drug delivery with reduced burst release
  • Implantable devices for drug delivery with reduced burst release
  • Implantable devices for drug delivery with reduced burst release

Examples

Experimental program
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example 1

Testing Implants in Canines

[0259]Implants were prepared by co-extrusion as described above and tested in two groups of dogs, with a third group of dogs serving as control. Each Group 1 dog (n=3) received three implants (30% ethyl cellulose shell / 60% T3 core; 26×2.4 mm; 75.8 mg T3), and were followed for about 8 months, including one week after removal of the implants. Each Group 2 dog (n=3) received three T3 implants (60% ethyl cellulose shell / 60% T3 core) on day 1, three additional T3 implants on day 87, and three additional T3 implants on day 118, for a dose-escalation study. The core of the T3 implants was about 2 mm in diameter, and the shell thickness was about 0.2 mm (twice the shell thickness is added to the core diameter to obtain the 2.4 mm diameter of the T3 implants). Control dogs (n=3) received EVA-based implants containing no thyroid hormones. The first implant was 4 cm in length and 3 mm in diameter; subsequent implants were 6 cm in length and 3 mm in diameter. Implant...

example 2

Testing T3 Implants in Thyroidectomized Rats

[0267]Administration of exogenous T3 results in a decrease in production of endogenous T3 by the thyroid. In order to get around the issue of endogenous T3 confounding the analysis of T3 release from implants, a thyroidectomized rat model with low background T3 was employed.

[0268]Each thyroidectomized rat (n=3) received one T3 implant (60% Ethocel Shell / 60% T3 Core; 40×3 mm) (ETHOCEL is a registered trademark of the Dow Chemical Company, Midland, Mich., United States, for ethyl cellulose polymer). The results are shown in FIG. 7, with comparison to normal rats. T3 release from T3 implants in thyroidectomized rats parallel that seen for these implants in normal rats. The assay upper limits of quantitation were capped at 1200 ng / dL. Implants were washed with ethanol prior to use.

[0269]The data for the normal rats receiving the 60% Ethocel Shell / 60% T3 Core implant is also shown in FIG. 12A and FIG. 12B, in comparison to normal rats receiving...

example 3

Ropinirole Implants in Dogs

[0270]Implants were prepared containing ropinirole. Implants with no shell (“core-only” implant) were prepared with 60% ropinirole in EVA, which were 2.4 mm in diameter and 26 mm in length. Two different sets of implants with shells were prepared. One set of shelled implants was prepared which was 40 mm long and 3 mm in diameter, having the same 2.4-mm-diameter 60% ropinirole in EVA core, and with a 0.3 mm-thick shell having 10% ETHOCEL in an EVA shell (twice the shell thickness is added to the core diameter to obtain the 3 mm diameter of these implants). The second set of shelled implants was similar, but was 60 mm long instead of 40 mm long. The implants were washed with ethanol prior to subdermal implantation. Three groups of male beagle dogs were used, with three dogs in each group. Three dogs received two implants each of the no-shell, core-only implant; three dogs received two implants each of the 40-mm-long implants with shell, and three dogs receiv...

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Abstract

The invention provides implantable drug delivery devices comprising a core comprising a polymer (or polymer blend) and one or more drugs or pharmaceutical substances, and an outer shell comprising a polymer (or polymer blend) and one or more porogen materials. The invention reduces burst release of drug. Pharmaceuticals such as triiodothyronine (T3) or ropinirole can be delivered by the devices.

Description

CROSS REFERENCE TO RELATED APPLICATIONS[0001]This patent application claims priority benefit of U.S. Provisional Patent Application No. 62 / 404,643 filed Oct. 5, 2016. The entire contents of that application are hereby incorporated by reference herein.TECHNICAL FIELD[0002]The invention provides devices which can be implanted into a patient for release of pharmaceutical substances, such as triiodothyronine, over long periods of time, with reduced, minimal, or no burst release.BACKGROUND OF THE INVENTION[0003]Many patients require long-term, regular dosing with drugs or pharmaceutical substances. Effective treatment often necessitates the ingestion of one or more tablets per day for extended periods of time. For example, patients who undergo thyroidectomy, a common treatment for thyroid cancer, must take oral thyroxine tablets for the rest of their lifetime. Typically, patients take levothyroxine (T4), which is converted in vivo into triiodothyronine (T3). Both T4 and T3 regulate a wid...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K9/00A61K9/48A61K31/197A61K31/4045A61K31/506A61K31/4458A61K38/26A61K31/485
CPCA61K9/0024A61K9/4808A61K31/197A61K31/4045A61K9/4816B29C48/21A61K31/4458A61K38/26A61K31/485A61K9/4833A61K31/506A61K9/145A61K9/146A61M31/002A61M37/0069A61P25/16A61K45/06A61K31/122A61K31/155A61K31/198A61K31/404A61K31/65A61K31/675A61K31/7068Y02A50/30A61K2300/00A61K9/0092A61K31/513B29C48/06B29K2001/08B29K2023/083B29K2105/0035B29K2995/006B29L2031/753
Inventor PATEL, RAJESH A.SREEDHARAN, SUNILBHONSLE, SUNIL R.
Owner FEDSON INC
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