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Oral pharmaceutical dosage forms

a technology of oral and syringe, which is applied in the direction of biocide, heterocyclic compound active ingredients, drug compositions, etc., can solve the problems of increasing the surface area of the tablet, the inside of the tablet, and the difficulty in maintaining control of the drug formulation, so as to enhance the in vivo pharmacological performance, enhance the methylphenidate delivery kinetics, and enhance the safety features and/or abuse resistance properties

Inactive Publication Date: 2010-10-14
DURECT CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0024]It is an advantage of the present invention that the controlled release oral dosage forms provide enhanced delivery kinetics of methylphenidate. It is also an advantage of the present invention that the abuse-resistant controlled release oral dosage forms are able to provide enhanced safety features and / or abuse-resistance properties in addition to enhanced in vivo pharmacological performance as compared with prior dosage forms. It is a further advantage of the invention that the inventive dosage forms can be readily constructed and used to provide a wide range of safer and more efficacious pharmacological solutions to the medical field. These and other objects, aspects and advantages of the present invention will readily occur to the skilled person upon reading the instant disclosure and specification.

Problems solved by technology

Formulation of drugs for delivery, particularly oral delivery, poses certain challenges.
One challenge is to produce an oral controlled-release dosage form that provides for a relatively steady dose of drug over the approximately eight hours during which the dosage form passes through the gastrointestinal tract.
A tablet, however, once ingested, is subject to considerable mechanical and chemical stresses as it passes through the esophagus, stomach, duodenum, jejunum, ileum, large intestine and colon, thus providing a significant challenge in maintaining controlled release of the drug formulation.
Acids, enzymes and peristalsis can cause the tablet to break apart, resulting in exposure of the inside of the tablet and an increase in surface area of the tablet material.
This will tend to increase the delivery rate of the drug or otherwise adversely affect the controlled release properties of the dosage form.
Another challenge is to produce a dosage form, including an oral dosage form, that reduces the potential for drug abuse.
The abuse of stimulants has been a growing problem.
A common and particularly dangerous cocktail of drugs is produced when stimulants are mixed with antidepressants or over-the-counter cold medicines containing decongestants.
Anti-depressants may enhance the effects of a stimulant, and stimulants in combination with decongestants may cause blood pressure to become dangerously high or lead to irregular heart rhythms, which in extreme cases may be fatal.
Solid dosage forms are particularly susceptible to abuse.
Administration of various abused drugs in this way produces a sudden high dose of drug into the blood stream making the user euphoric.
Other characteristics may include aggressiveness, stealing, lying, truancy, setting fires, running away, explosiveness, cognitive and learning problems as well as poor social skills.

Method used

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Examples

Experimental program
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Effect test

example 1

Preparation of Formulations

[0197](GMP Manufacturing Process)

[0198]A GMP manufacturing process for the dosage forms of the present invention was developed and carried out as follows. The following raw materials were used to create the formulations: methylphenidate (“MPH”); Isopropyl Myristate, NF (“IPM”); Colloidal silicon dioxide (Cabosil®, Cabot Corp) (“SiO2”); Butylated hydroxyl toluene, NF (“BHT”); Hydroxyethyl cellulose, NF (“HEC”); Sucrose Acetate Isobutyrate (Eastman Chemicals), (“SAIB”); Triacetin USP (“TA”); Cellulose Acetate Butyrate, grade 381-20 BP, ethanol washed (Eastman Chemicals) (“CAB”); Gelucire 50 / 13 (Gattefosse) (“GEL”); and Miglyol 812 (“MIG”). The formulations were filled into size #3 gelatin capsule shells. The specific details for the three different formulations produced using the GMP manufacturing processes of this Example 1 are disclosed below in Tables 1 and 2. The batch sizes were up to 500 g.

TABLE 1Formulation by Weight Percent (wt %)MPH1MPH2MPH3MPH11MPH...

example 2

Analysis of Formulations

[0200](In Vitro Dissolution Testing Procedures)

[0201]Two in vitro dissolution test methods were developed in order to assess the controlled release performance of abuse-resistant dosage forms produced according to the present invention such as the methylphenidate dosage forms recited herein. The first dissolution method (Method 1) was based upon USP Method A for delayed-release dosage forms and uses an USP dissolution apparatus Type 2 (without basket) with a two-stage media (an initial volume of 750 mL of 0.1N HCl acid as the dissolution medium, followed by adjustment to pH 6.8 by addition of 250 mL of sodium phosphate buffer after 2 hours). The two-stage media was selected to simulate the pH range over which a dosage form will release active agent during transit through the GI tract. Stainless steel coiled wire type 316 is used as a sinker to ensure that the dosage forms remain at the bottom of the dissolution vessel during release rate testing.

[0202]The se...

example 2a

[0208]The following in vitro dissolution test was carried out to characterize the in vitro release of abuse-resistant methylphenidate oral dosage forms across several different formulations.

[0209]The abuse-resistant methylphenidate oral dosage forms used in this Example 2a were prepared using the following raw materials: methylphenidate (“MPH”); Isopropyl Myristate, NF (“IPM”); Colloidal silicon dioxide (Cabosil®, Cabot Corp) (“SiO2”); Butylated hydroxyl toluene, NF (“BHT”); Hydroxyethyl cellulose, NF (“HEC”); Sucrose Acetate Isobutyrate (Eastman Chemicals), (“SAIB”); Triacetin USP (“TA”); Cellulose Acetate Butyrate, grade 381-20 BP, ethanol washed (Eastman Chemicals) (“CAB”); Gelucire 50 / 13 (Gattefosse) (“GEL”); and Miglyol 812 (“MIG”). The formulations were produced using the manufacturing process as described in Example 1 above, and then filled into size #3 gelatin capsule shells to produce the dosage forms that were used as Test Capsules. The details of the formulations and the ...

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PUM

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Abstract

Controlled release oral dosage forms suitable for administration of methylphenidate are provided. Abuse-resistant controlled release oral dosage forms suitable for administration of methylphenidate are also provided. Methods of treating ADD and ADHD using the oral dosage forms are also provided.

Description

CROSS REFERENCE TO RELEVANT APPLICATIONS[0001]This application claims the priority entitlement and full benefit of U.S. Provisional Application Nos. 61 / 198,244, filed 3 Nov. 2008, and 61 / 201,015, filed 5 Dec. 2008, pursuant to 35 U.S.C. §119(e).FIELD OF THE INVENTION[0002]The invention relates to oral pharmaceutical dosage forms and the use thereof. More specifically, this invention relates to controlled release oral pharmaceutical dosage forms and their use to deliver methylphenidate.BACKGROUND[0003]Formulation of drugs for delivery, particularly oral delivery, poses certain challenges. One challenge is to produce an oral controlled-release dosage form that provides for a relatively steady dose of drug over the approximately eight hours during which the dosage form passes through the gastrointestinal tract. Sustained release is often achieved by providing the tablet with a coating that delays release, or by formulating the tablet in such a way that it disintegrates relatively slowl...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/445A61K9/00A61P25/00
CPCA61K9/1617A61K9/1623A61K9/4808A61K9/0053A61K9/5084A61K31/4458A61K9/4858A61P25/00
Inventor SCICINSKI, JAN J.VAN OSDOL, WILLIAM W.SU, HUEY-CHINGARENBERG, MICHAEL H.SHAH, JAYMIN
Owner DURECT CORP
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