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(19) United States (12) Patent Application Publication (10) Pub US 20060018934A1 (19) United States (12) Patent Application Publication (10) Pub. N0.: US 2006/0018934 A1 Vaya et al. (43) Pub. Date: Jan. 26, 2006 (54) NOVEL DRUG DELIVERY SYSTEM (30) Foreign Application Priority Data (76) Inventors; Navin Vaya, Gujarat (IN); Rajesh Aug. 5, 2002 (IN) ............................... .. 698/MUM/2002 Singh Karan, Gujarat (IN); Suni] Aug. 5, 2002 (IN) .... .. 696/MUM/2003 Sadanand Nadkarni, Gujarat (IN); Jan. 22, 2003 (IN) ................................. .. 81/MUM/2003 Vinod Kumar Gupta, Gujarat (IN) Publication Classi?cation Correspondence Address: HEDMAN & COSTIGAN RC. (51) Int. Cl. 1185 AVENUE OF THE AMERICAS A61K 9/00 (2006.01) NEW YORK, NY 10036 (US) A61K 9/24 (2006.01) (52) US. Cl. .......................................... .. 424/400; 424/472 (57) ABSTRACT (21) Appl. No.: 11/134,632 A novel modi?ed release dosage form comprising of a high (22) Filed: May 19, 2005 solubility active ingredient, Which utilizes dual retard tech nique to effectively reduce the quantity of release controlling Related US. Application Data agents. Present invention can optionally comprise addition ally another active ingredient as an immediate release form (63) Continuation-in-part of application No. 10/630,348, or modi?ed release form. Present invention also relates to a ?led on Jul. 29, 2003. process for preparing the said formulation. Patent Application Publication Jan. 26, 2006 Sheet 1 0f 5 US 2006/0018934 A1 FIGURE 1 (a) FIGURE 1 (b) Patent Application Publication Jan. 26, 2006 Sheet 2 0f 5 US 2006/0018934 A1 FIGURE 2 120 — (95) 100 80 60 ActiveIngredientRelease 4O - 2O - 0 2 4 6 8 10 12 14 16 18 2O 22 24 Q 26 Time (hour) Patent Application Publication Jan. 26, 2006 Sheet 3 0f 5 US 2006/0018934 A1 120 - (%) 100. 80 - IngredientReleaseActive 60 — 4O - 20 O 2 4 6 8 10 l2 14 16 18 2O 22 24 26 Time (hour) Patent Application Publication Jan. 26, 2006 Sheet 4 0f 5 US 2006/0018934 A1 FIGURE 4 120 - 14 100 15 ' so_ / 16 13 ReleaseActiveIngredient 60 40 20 0 2 4 6 8 - 1O 12 14 Time (hour) Patent Application Publication Jan. 26, 2006 Sheet 5 0f 5 US 2006/0018934 A1 FIGURE 5 1600 1400 1200 - :E\@5co?umupcmucoomEwmHm 1000 2846 0O O0 Time [Hours] US 2006/0018934 A1 Jan. 26, 2006 NOVEL DRUG DELIVERY SYSTEM [0006] One method of prolonging the release of a highly Water-soluble drug is disclosed PCT Patent application no. [0001] This application is a continuation-in-part of WO99/47128. Abiphasic controlled release delivery system 10/630,348, ?led Jul. 29, 2003. for metformin hydrochloride, Which has prolonged gastric residence and that sWells folloWing hydration. The ratio of FIELD OF INVENTION inner solid phase to outer continuous phase is 0.5 :1 to about [0002] This invention relates to a modi?ed release dosage 4:1. The major limitation of this invention is that it provides form comprising of a high solubility active ingredient, a very bulky formulation for higher doses of the metformin Which utiliZes dual retard technique to effectively reduce the hydrochloride that is very inconvenient for human consump quantity of release controlling agents. Present invention can tion. For instance, example cited provides formulation of optionally comprise additionally another active ingredient as 500 mg metformin hydrochloride With tablet Weight of 1.0 an immediate release form or modi?ed release form. Present gm. Hence restricting to the loW dose sustained release invention also relates to a process for preparing the said tablets of 500 mg or slightly more and making it obligatory formulation. to take tWo tablets of 500 mg each time to provide sustain action. The cited example teaches use of combination of BACKGROUND OF THE INVENTION atleast one hydrophilic polymer and Which is a essential part for sWelling. Non sWellable or nonerodeble formulations are [0003] It is Well knoWn to those skilled in the art that the not included in the invention. blood levels of drugs need to be maintained above a mini mum effective level and beloW its minimum toxic level in [0007] PCT application No. WO 02/28181 A1 describes a order to obtain the desired therapeutic effects and to mini monolithic sustained release formulation of metformin miZe side effects. Unfortunately, the pharmacokinetic prop hydrochloride. The method of making the formulation erties (absorption, elimination and metabolism) of most involves hot melt granulation folloWed by Wet granulation drugs are such that they need to be administered three to four With binders or extrusion. The formulation essentially times a day. This kind of a dosing regimen is very incon requires binder and auxiliary pharmaceutically acceptable venient and leads to reduction in patient compliance. Reduc excipients. The formulation consists of metformin hydro tion of dosing regimen from three times a day (t.i.d.) to tWice chloride polymer and or hydrophobic material. The dosage daily (bid) to once a day results in increased convenience form release more than 90% of the drug Within 8 hours. and comfort and therefore increased patient compliance. Drugs that are administered in the form of conventional [0008] Similarly US. Pat. No. 6,340,475 B2 assigned to tablets of capsules become available to body ?uids at a rate Depomed Inc. describes monolithic controlled release for that is initially very high, folloWed by a rapid decline. For mulation of highly Water soluble drugs including metformin many drugs, this delivery pattern results in a transient hydrochloride. The formulation sWells When ingested thus overdose, folloWed by a long period of under dosing. This is prolonging its residence time in the stomach. The formula a pattern of limited clinical usefulness. The delivery pattern tions are made of hydrophilic polymers, Which results in Was improved in the 1970’s With the introduction of a sWellable and erodible matrix. variety of modi?ed delivery systems. Modi?ed release for [0009] Another method of prolonging the release of a mulations, Which are effective in maintaining the therapeutic highly Water-soluble drug is disclosed in International Patent blood levels over, extended periods of time result in optimal application publication no. WO 96/26718, published Sep. 6, therapy. They not only reduce the frequency of dosing, but 1996. The method of this publication is the incorporation of they also reduce the severity and frequency of side effects, the drug into a polymeric matrix to form a tablet that is as they maintain substantially constant blood levels and administered orally. The polymer is Water-sWellable yet avoid the ?uctuations associated With the conventional erodible in gastric ?uids. immediate release formulations administered three to four times a day. [0010] Similarly Chih-Ming Chen in international patent application number WO 02/36100 describes a once a for [0004] There are a number of different modi?ed release mulation of metformin hydrochloride Which is based on dosage forms available commercially. HoWever, some of osmotically controlled technique and that is non expandable these are expensive to manufacture and can be dif?cult to in nature and has a passage in the coating membrane for sWalloW, particularly in elderly patients. Many of these release of drug. modi?ed delivery systems utiliZe hydrophilic, polymeric matrices that provide useful levels of control to the delivery [0011] Kim et al. in US. Pat. No. 6,337,091 describes a of sparingly soluble drugs. For soluble drugs, hoWever, and matrix based controlled release formulation for highly particularly for highly soluble drugs, such matrices do not soluble drugs over long periods of time. The release con provide adequate control over the release rate, instead result trolling agent is a sWellable gum Which encapsulates or ing in a release that approximates ?rst-order kinetics and make granules of drug, Which is then disposed in more may have a problem of dose dumping or burst release. sWellable erodible polymers such as HPMC or poly(ethyl HoWever, since many modi?ed release dosage forms contain eneoxide). comparatively large amounts of active ingredient it is often [0012] These systems can provide for modi?ed release for necessary to include large amounts of suitable excipients to achieve appropriate controlled release pro?les. Clearly, this selected active ingredients like active ingredients With loW dose or loW Water solubility. HoWever, When a highly Will tend to increase the siZe of the dosage form. soluble or high dose active ingredient is used, most of these [0005] The various techniques to make modi?ed release systems have the disadvantages such as comparatively loW dosage form of drugs as described in prior art are as payload of active ingredient thus making dosage form bulky folloWs— and expensive or lead to burst effect or prolonged release of US 2006/0018934 A1 Jan. 26, 2006 active ingredient for a shorter duration or use of complex [0024] The present invention also provides a novel process manufacturing procedure and/or equipment. for preparing the novel formulations of the invention. [0013] There exists a need for compositions and process [0025] The present invention further provides a method of for making orally deliverable dosage form containing highly treating an animal, particularly a human in need of treatment soluble active ingredient as modi?ed release that overcomes utiliZing the active agents, comprising administering a thera the problems discussed above. This invention addresses the peutically effective amount of composition or solid oral need. dosage form according to the invention to provide admin istration of active ingredients. [0014] Therefore, it Would be of considerable clinical bene?t to design a dosage form With high pay load of highly DETAILED DESCRIPTION OF THE soluble active ingredient that Would be much easier for the INVENTION patient to sWalloW. This type of technology could also be used to reduce the siZe of many existing drug formulations.
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