Oral dosage forms for oxygen-containing active agents and oxyl-containing polymer

a technology of oxyl-containing polymer and oral dosage form, which is applied in the direction of drug compositions, biocide, heterocyclic compound active ingredients, etc., can solve the problems of short-acting commercially available combination products, delayed recovery process, and difficulty in sleeping

Inactive Publication Date: 2014-06-26
SPRIASO
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention provides a pharmaceutical tablet that includes a tri-oxy active agent and a release-rate controlling non-ionic oxyl-containing hydrophilic polymer, which results in a matrix tablet with no negative food effects that can be taken every 12 hours. The tablet includes a unique optimal oxyl content that ensures a 12-hour product with no food effect. The combination tablet can be used for oral dosing once every 12 hours and provides a steady release of the active agents over a longer period of time. The tablet can be administered without a meal and provides a consistent blood level of the active agents over a 12-hour period. The technical effect of the invention is the development of a pharmaceutical tablet with improved bioavailability and consistent release of the active agents over a longer period of time.

Problems solved by technology

However, these combinations are primarily available as inconvenient liquids which are prone to dosing errors and which require frequent dosing in order to provide consistent and continuous symptom relief.
Commercially available combination products tend to be short-acting and often require dosing every four, six or eight hours.
The need for frequent dosing and the re-emergence of symptoms between doses often make sleeping difficult, which in turn can delay the recovery process.
However, such very slow release profile is unsuitable for a 12 hour dosing therapy of tri-oxy actives to allow sleeping through the night and without excessive daytime grogginess.
However, such a slow release profiles for tri-oxy actives is unsuitable for a 12 hour dosing therapy.
Due to tremendous safety liability associated with deviations from acceptable peak blood concentrations, many tri-oxy active agents, such as narcotics like codeine and hydrocodone, require stable blood levels upon oral dosing.
For a solid dosage form (tablet, capsules etc.) containing multiple actives with a hydrophilic polymer, the design and management of the dosage form performance for a given intended use becomes increasingly challenging.
This is especially true with regards to efficacy, release, and pharmacokinetic requirements, which can be further complicated for each active due to its distinct physiochemical and biological properties.
Additionally, food interactions with an oral dosage form upon ingestion can produce unacceptable higher blood concentrations of actives, especially from a longer acting product which has higher active strength per dosage unit relative to an immediate release dosage form.

Method used

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  • Oral dosage forms for oxygen-containing active agents and oxyl-containing polymer
  • Oral dosage forms for oxygen-containing active agents and oxyl-containing polymer
  • Oral dosage forms for oxygen-containing active agents and oxyl-containing polymer

Examples

Experimental program
Comparison scheme
Effect test

example 1

In Vitro Release Profiles of the Actives from Dosage Forms

[0100]The in vitro release profiles of the respective actives from the dosage form examples of the current invention were determined using a USP Type II (paddle) Dissolution Apparatus set at 50 rpm in about 900 mL of 0.1N hydrochloric acid solution in water at about 37° C. Aliquots sampled from the dissolution apparatus at pre-determined time intervals varying from about 5 minutes up to about 36 hours were analyzed for the respective actives by employing an HPLC with a UV spectrophotometer detector and using appropriate standard solutions. The amount of the active released is then calculated from the concentrations of actives in the medium and the volume of the medium, and expressed as a percentage of their amounts originally present in the dosage form.

example 2

In Vivo Pharmacokinetic Evaluation of the Dosage Forms

[0101]Dosage forms of examples where indicated, were evaluated for in vivo pharmacokinetic performance. The general study design was an open-label, randomized, single-dose, crossover performed on 10-12 volunteers. In each treatment period, subjects were housed from at least 12 hours before dosing until after the 24-hour blood draw. There was at least 5-day washout between treatment periods, during the study. The analysis of the plasma samples were carried out for the respective drugs using LC-MS / MS.

[0102]The Cmax, Tmax, AUC0-t and AUC0-∝ were calculated for the first and second actives in the plasma of the test subjects. Pharmacokinetic and statistical analyses were performed on the data obtained from the subjects using Pharsight® WinNonlin®. The pharmacokinetic parameters are defined as follows:[0103]AUC0-t: The area under the plasma concentration vs. time curve, from zero time to last measurable concentration of the drug, as ca...

example 3-15

Dosage Forms Having at Least One Tri-Oxy Active and at Least One Oxyl-Containing Non-Ionic Hydrophilic Polymer

[0110]Tablet dosage forms having the compositions as recited in Examples 3 through 15 are prepared by using the respective components shown in Tables I and II.

TABLE IEXAMPLEINGREDIENT*345678910First Active (Tri-oxy active),5454545454545454mg[e.g. Codeine Phosphate, CP]Second Active (Non-oxo88888888active), mg[e.g. ChlorpheniramineMaleate, CPM]Oxyl-containing non-ionic25752004506585—50hydrophilic polymer, mg [e.g.Hypromellose 2208]Oxyl-containing non-ionic——————5719hydrophilic polymer, mg [e.g.Hypromellose 2910]Pharmaceutical Processing656510516075657380Aids, mgTotal Methoxyl Content of the0.190.561.503.370.490.640.580.57non-ionic hydrophilic polymer,(mMol.)Total Hydroxyl Content of the0.130.401.082.420.350.460.310.37non-ionic hydrophilic polymer(mMol.)Total Oxyl Content of the non-0.320.972.575.790.841.090.890.94ionic hydrophilic polymer(mMol.)Total Molar Content of the0.410...

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Abstract

The disclosed invention is drawn to pharmaceutical tablets that provide delivery of active agents having at least three oxygen-containing groups, as well as a second active ingredient. Non-limiting examples of three oxygen-containing group active agents include guaifenesin, codeine, hydrocodone, and their pharmaceutically acceptable salts. In one embodiment, a pharmaceutical tablet for oral administration once every 12 hours is provided. The tablet includes a first active agent that is a tri-oxy active agent, a second active agent, and a release rate controlling non-ionic oxyl-containing hydrophilic polymer. The total oxyl content of the hydrophilic polymer in the tablet is about 4×10−4 moles to about 2.0×10−3 moles.

Description

[0001]This application is a continuation of U.S. patent application Ser. No. 13 / 342,883, filed Jan. 3, 2013, which is herein incorporated by reference.FIELD OF THE INVENTION[0002]The present invention relates to oral dosage forms containing combination of pharmaceutical active agents for treating cough and associated methods of treatment and manufacture. Accordingly, this invention involves the fields of chemistry, pharmaceutical sciences, medicine and other health sciences.BACKGROUND OF THE INVENTION[0003]Tri-oxy active agents (drugs having at least three different oxygen-containing groups) such as guaifenesin, codeine and hydrocodone are used to treat cold and cough as well as other related symptoms. Often, cold, cough, allergies, and other similar conditions can require treatment with multiple active agents in order to simultaneously alleviate multiple symptoms. For example, combinations of active agents such as codeine or hydrocodone with a mucolytic or a decongestant or an anti...

Claims

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Application Information

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Patent Type & AuthorityApplications(United States)
IPC IPC(8): A61K9/20A61K31/4402A61K31/137A61K31/485
CPCA61K9/2054A61K31/09A61K31/137A61K31/194A61K31/4402A61K31/485A61K45/06A61P11/00A61P11/02A61P11/14A61K2300/00A61K9/0053
InventorGILIYAR, CHANDRASHEKARNACHAEGARI, SATISH KUMARNACHIAPPAN, CHIDAMBARAMPATEL, MAHESH V.VENKATESHWARAN, SRINIVANSAN
OwnerSPRIASO