WO2009087665A2

WO2009087665A2 - Novel gastroretentive drug delivery system

Info

Publication number: WO2009087665A2
Application number: PCT/IN2008/000817
Authority: WO
Inventors: Vishwanath Sudhir Nande
Original assignee: Vishwanath Sudhir Nande
Priority date: 2007-12-11
Filing date: 2008-12-08
Publication date: 2009-07-16
Also published as: WO2009087665A3

Abstract

A novel gastro-retentive drug delivery system is presented that floats over the simulated physiological fluids owing to its low density. The said floating delivery system comprises inert core, polymers and plasticizer. The said delivery system retains its floating property over an extended period of time.

Description

NOVEL GASTRORETENTIVE DRUG DELIVERY SYSTEM

DESCRIPTION

FIELD OF THE INVENTION

This invention relates to a novel method of preparing polymeric devices that floats over simulated gastro-intestinal fluids for an extended period of time. These devices can be used for local or systemic effects of the active ingredient it contains.

BACKGROUND

The preferred route of administration of most of the drugs is via the gastrointestinal tract. Most drugs are well absorbed throughout the gastrointestinal tract but some of the drugs due to their polar nature are poorly absorbed from the large intestine; small intestine being their site of absorption or 'absorption window'. The window could represent the duodenum, the jejunum or the ileum or the parts thereof. It would therefore be advantageous to hold these drugs in the stomach i.e. above their main site of absorption for extended period of time to attain complete drug absorption. There are some drugs, weakly acidic drugs, which have their site of absorption in the stomach where they are present in non-ionized form. For exerting local effects in the stomach, like use of antibiotics for the treatment of Helicobacter pylori (H. pylori), gastro-retentive systems provide the best suitable option. For all the cases as mentioned above gastro- retentive drug delivery system is the system of choice for formulating these drugs into dosage forms.

US patent 3,976,764 describes the process of making floating drug delivery system using empty sells and hard gelatin capsules. X-ray study revealed the presence of the dosage form in the upper GI tract for extended period. The dosage form was however difficult to manufacture on large scale.

The topic of gastro-retentive dosage forms as been thoroughly reviewed by Moes (Crit. Rev. Ther. Drug Carrier Syst., 1, 143 (1993)) and Deshpande et al (Drug Delivery and Industrial Pharmacy, 22, 531 (1996)). Proposed methods described in these review articles for prolonging the gastric residence time of drug delivery systems include agents such as fatty acids, pharmacological agents which delay the passage of material from the stomach to the small intestine, and devices such as unfolding polymer sheets and balloon hydrogels (Park, K. and Park, Proc. Int. Symp. Control. ReI. Bioact. Mater., 14, 41 (1987). Another way of attaining gastro-retention is by means of non-disintegrating dosage form having sizes between 7mm to 20mm. This delivery device does not exit the stomach till the stomach is empty of food.

It would also be prudent to add bio-adhesive polymers to these delivery devices. These polymers would increase the residence time of these devices in the stomach by several minutes to a few hours Longer, M.A.. Chang, .S. and Robinson, J. R., J. Pharm. ScL 74, 406 (1985). Tablets and pellets with increased gastric retention and bio-adhesive properties have been described in international patent application WO 94/00112. The specific use of micro-adherent formulations in the treatment of gastric disorders (including H. pylori) has been described in international patent application WO 92/18143. Floating mini capsules, having a size 0.1 to 2 mm, containing sodium bicarbonate, and which are coated by conventional water-soluble film coating agents is described in U.S. Pat. No. 4,106,120. Similar floating granules based on gas generation have been described in U.S. Pat. No. 4,844,905.

European patent application EP 635261 describes coated microparticles with improved drug absorption which consist of dehydrated microparticles comprising a nucleus of a gellable hydrocolloid onto which is deposited a film of cationic polysaccharide. The microparticles described in this document promote the absorption of drugs from the intestine.

By using all these prior arts floating drug delivery devices could be prepared. However there are chances that some of the dosage forms prepared using these principles might still not float. Non-uniformity in distribution of excipients during manufacturing or uneven physical characteristics of individual units may contribute to these effects. A sudden drug release or drug release in undesired part of the gastro intestinal tract would render these delivery devices unsuccessful apart from exposing the person to undesirable side effects. Thus, in summary, it would be of benefit to provide a system for delivering drug to the stomach, which possessed the following attributes,

(a) a significant retention time in the fasted stomach of mammalian (e.g. human) subjects

(b) a high loading of water soluble and lipid soluble drugs

(c) a controlled release of such drugs over a period of time that is relevant to the clinical need (ie delivery of drug to the stomach, and/or enhanced drug uptake from an absorption window in the small intestine).

Other desirable attributes include:

(a) the preparation of such a formulation using established pharmaceutical processing methods and

(b) the use of materials in the preparation of such a formulation that are approved for use in foods or pharmaceuticals or of like regulatory status.

DESCRIPTION OF FIGURES

Fig. 1 : Schematic representation of the preparation and subsequent operations over substrates.

Fig. 2: Dissolution apparatus used in the investigation. Schematic representation of modified dissolution apparatus: 1 -Dissolution vessel, 2-shaft, 3-paddle, 4-dissolution media, 5-basket, 6- hollow polymeric sells, 7-assembly for holding the basket in place

Fig. 3: Dissolution profile of Ciprofloxacin HCl

Fig. 4: Dissolution profile of Propranolol HCl

DESCRIPTION OF INVENTION

Process of hydration as described in the present invention refers to placing the coated sugar spheres in water for sufficient time such that sugar from the core diffuses out partly or completely.

Substrates as described in the present invention is a housing that is partially or completely hollow from inside and capable of floating over water and which may be a single unit or multiple unit. taken care that all the individual units remain buoyant. It is a prior art to coat substrates like pellets and tablets using different families of polymers to attain the desired properties. Film coating is done to provide aesthetic value, extend release of active medicament from the core over a period of time, provide moisture barrier, release the active at specific site in the gastro-intestinal tract (GIT) and protect the active from gastric environment. The polymers used for the this purpose are not limited to cellulose derivatives, acrylic acid polymers, polyvinyl pyrrolidone, polyvinyl alcohol to achieve the desired property. These polymers are applied over the substrates using solvent spraying and evaporation method using a solvent or combination of solvents to get films of desired thickness. Waxes like hydrogenated castor oil, hydrogenated vegetable oil, glyceryl monostearate etc. can also be applied over the substrates using solvent evaporation or melting method.

Preparation of substrates

Sugar spheres (25#-30#) were coated with a combination of hypromellose 2910 (HPMC E 5) and Ethylcellulose N 50 or Eudragit® RLPO and Eudragit® RSPO. In one case Cellulose acetate 398 10 NF and Eudragit® RSPO were used for coating. Typically the coating composition included HPMC E 5: Ethocel N 50 (15:85), PEG 400, talc, isopropyl alcohol and methylene chloride. In another cast the coating composition included Eudragit® RLPO: Eudragit® RSPO (50:50), triethyl citrate, talc, acetone and isopropyl alcohol. In another case the coating composition included cellulose acetate 398 10 NF: Eudragit® (85:15), PEG 400, acetone and water. The coating was carried out in local made coating pan (non-perforated), nozzle diameter 0.5mm, atomization air pressure 15-25k/cm2, spray rate 1-15/min and bed temperature 25-32°C. Curing of the coated spheres was carried out at 40°C for 24hours.

To remove sugar from the core, the coated spheres were put in water for sufficient period of time. Water from the out side enters into the core by diffusing trough the coat. Water-soluble material present in the coat dissolved slowly thereby creating pores or cannels trough which water from out side entered into the core. When Eudragit® RS/RL combination was used, the entrance of water into the core was due to loss of the plasticizer (triethyl citrate) and through the water cannels formed due to ionization of the It is scientifically well acknowledged that any object that has air entrapped inside have a tendency to float over water. Tennis balls, air filled rubber tubes, a tightly closed box all have natural propensity to float over water. These materials owe this property to the air trapped into them. The entrapped air provides the necessary buoyant force to these materials that allows them to float over water. Even if these objects are overweight, or if some material is added over tem would still retain their floating property. These objects continue to float as long as air remains entrapped into tem. When the air gets leaked out, the floating property of these objects depends upon the density of their material of construction; if lit would still float over water.

The concept of present invention came from observations of coated sugar spheres at the end of routine dissolution study. At the end of dissolution study of extended release pellets prepared using sugar spheres, a few empty polymeric shells were found floating in the dissolution vessel. Close observations revealed that some of these shells had retained their spherical structure and dissolution media was found entrapped into them. These water-filled shells were carefully removed from the vessel, placed over filter paper and allowed to air dry. Water from inside diffused onto the paper and the shells lost their spherical shape. These distorted structures when again put into water floated over it for more than 48 hours. This experiment gave enough idea that such shells when properly formed should retain their structure while remain floating over extended period of time.

Fig. 1 describes the processes involved in the manufacturing of final dosage form. Typically the processes involved in the present invention include coating of polymers over water soluble inert cores, hydrating these cores for suitable time to allow diffusion out of the water soluble inert material, removal of water from inside the shells, drying of the shells for suitable time and optionally applying a polymeric film over these dried empty polymeric shells. Suitable candidates for drug delivery can be applied over these empty polymeric shells by coating either along with polymer or wax or combinations of polymers or waxes or polymers and waxes. Optionally a bio-adhesive polymer may be applied over these drug-containing shells.

The main thrust of the present invention was to develop gastro retentive devices that possess floating properties throughout the time period tested. It was also ionizable groups. Initially as the core sugar dissolves in diffused water, a saturated sugar solution is formed. The dissolved sugar moves out into the vessel due to concentration gradient. Water in the vessel needed periodic replacement to ensure that the concentration gradient of sugar across the film was maintained. As sugar moves out of the water-filled polymeric shells their density decreases and may start floating over water surface. Typically it took between 48-72 hours for sugar to move out of the core. At the end of hydration phase some shells were found floating in the vessel while rest were placed at the bottom. These water-filled polymeric shells were carefully placed over filter paper and kept for 24 hours during which water moves out of the core. These shells were then placed in a tray dryer for 48 hours to dry-out the remaining water from the core. Optionally mild agitation and/or warm water may be used to fasten sugar diffusion. These substrates when cut showed presence of sugar - from traces to a substantial quantity. This observation indicates that even when the substrates were partly empty, they still had floating property. The floating property of these substrates were due to the entrapped air and not on the amount of sugar diffused out of the shells. The shape of these dried shells was similar to that of the initial inert material.

The film coating over sugar spheres played very important role in the process of hydration and final geometry of the hollow shells. When the coating extent was low, the film thickness was less that made the time for sugar loss from core sort but after drying these water-filled polymeric shells lost their shape and geometry. When the coating extent was high, the film thickness was more that made the process of sugar loss lengthier but helped to retain their shapes after drying. The coating composition had similar effect - films with high water-soluble materials produce lost the sugar fast but lost their shapes while those with less water-soluble materials retained their structure but had extended period of time for sugar removal. Typically the coating extent was between 3-15%, more preferably between 5-10%.

The dried polymeric shells by themselves had very low density that gave them natural tendency to float over water. The substrates had pores through which sugar had diffused out. To make the surface of these substrates non-porous, a water insoluble polymer, Ethocel N 50, was applied over them. A thin film of this polymer over these substrates ensured smooth continues surface under which air had been entrapped. The non-porous nature of this film means that under normal operational conditions the entrapped air does not leak out. The coating was carried out in local made coating pan (non-perforated), gun nozzle diameter 0.5mm, atomization air pressure 1.5-2.5 k/cm2, spray rate 1-1.5 /min, bed temperature 25-30°C. These coated shells were cured in tray dryer for 24 hours at 40°C.

Examples of preparation of substrates Example 1

Sugar spheres (25/30) 50g, were coated with HPMC E5 (1.5g), Ethocel N 50 (8.5g), PEG 400 (1.Og), talc (1.Og), isopropyl alcohol and methylene chloride till the weight gain of 7% w/w and cured in tray dryer for 24hours at 40°C. These coated sugar spheres were put in 500ml water contained in a vessel with mild agitation. After every 12 hours water in the vessel was replaced with fresh water. At the end of 48 hours, the water filled polymeric enclosures were carefully filtered, washed with sufficient quantity of water and placed over filter paper. After 40 hours, the semi-dried hollow polymeric shells were put into tray dryer and dried for another 24 hours at 40°C. The substrates (5g) were ■ coated with Ethocel N 50 (0.5g), dibutyl phthalate (0.05g), talc (0.05g), isopropyl alcohol and methylene chloride and cured in tray dryer for 24 hours at 40⁰C.

Example 2

Sugar spheres (25/30) 50g, were coated with HPMC E5 (2.Og), Ethocel N 50^" (8.0g), PEG 400 (1.Og), talc (1.Og), isopropyl alcohol and methylene chloride till the weight gain of 7% w/w and cured in tray dryer for 24hours at 40°C. These coated sugar spheres were put in 500ml water contained in a vessel with mild agitation. After every 12 hours water in the vessel was replaced with fresh water. At the end of 40 hours, the water filled polymeric enclosures were carefully filtered, washed with sufficient quantity of water and placed over filter paper. After 40 hours, the semi-dried substrates were put into tray dryer and dried for another 24 hours at 40°C. The substrates (5g) were coated with Ethocel N 50 (0.3g), dibutyl phthalate (0.03g). talc (0.03 g), isopropyl alcohol and methylene chloride and cured in tray dryer for 24 hours at 40°C.

Example 3

Sugar spheres (25/30) 50g, were coated with Eudragit® RSPO (7.5g), Eudragit® RLPO (2.5g), triethyl citrate (1.Og), talc (1.Og), isopropyl alcohol and methylene chloride till the weight gain of 5% w/w and cured in tray dryer for 24hours at 40°C. These coated sugar spheres were put in 500ml water contained in a vessel with mild agitation. After eveiy 12 hours water in the vessel was replaced with fresh water. At the end of 72 hours, the water filled polymeric enclosures were carefully filtered, washed with sufficient quantity of water and placed over filter paper. After 24 hours, the semi-dried substrates were put into tray dryer and dried for another 24 hours at 40°C. The substrates (5g) were coated with Ethocel N 50 (0.3g), dibutyl phthalate (0.03g), talc (0.03g), isopropyl alcohol and methylene chloride and cured in tray dryer for 24 hours at 40°C.

Example 4

Sugar spheres (25/30) 30g, were coated with Eudragit® RSPO (5g), Eudragit® RLPO (5g), triethyl citrate (1.Og), talc (1.Og), isopropyl alcohol and methylene chloride till the weight gain of 8% w/w and cured in tray dryer for 24hours at 40°C. These coated sugar spheres were put in 500ml water contained in a vessel with mild agitation. After every 12 hours water in the vessel was replaced with fresh water. At the end of 60 hours, the water filled polymeric enclosures were carefully filtered, washed with sufficient quantity of water and placed over filter paper. After 24 hours, the semi-dried substrates were put into tray dryer and dried for another 24 hours at 40°C. The substrates (5g) were coated wit Ethocel N 50 (0.3g), dibutyl phthalate (0.03g), talc (0.03g), isopropyl alcohol and methylene chloride and cured in tray dryer for 24 hours at 40°C.

Example 5

Sugar spheres (25/30) 4Og, were coated with Cellulose acetate (8.5g), Eudragit® RSPO (1.5g), PEG (1.Og), talc (1.Og), isopropyl alcohol and acetone till the weight gain oi bVo w/w and cured in tray dryer lor 24hours at 40°C. These coated sugar spheres were put in 500ml water contained in a vessel with mild agitation. After every 12 hours water in the vessel was replaced with fresh water. At the end of 36 hours, the water filled polymeric enclosures were carefully filtered, washed with sufficient quantity of water and placed over filter paper. After 24 hours, the semi-dried substrates were put into tray dryer and dried for another 24 hours at 40°C. The substrates (6) were coated with hydrogenated castor oil (0.5g), Eudragit® RSPO (O.lg), dibutyl phthalate (0.03g), talc (0.03g), acetone and water and cured in tray dryer for 24 hours at 35°C.

Examples of drug-layering over substrates

Substrates prepared from the combination of cellulose acetate and Eudragit® RSPO were used for drug-layering. The examples are as given under.

Example 1

Ciprofloxacin hydrochloride was dissolved in aqueous solution of HPMC E5 along with PEG 400 and talc. The coating was carried out in local made coating pan (non- perforated), gun nozzle diameter 0.5mm, atomization air pressure 1.5-2.5 k/cm2, spray rate 1-1.5 /min, bed temperature 35-40⁰C. These coated shells were cured in tray dryer for 24 hours at 40⁰C. Eudragit® RSPO and RLPO (50:50), triethyl citrate, talc, acetone and isopropyl alcohol were applied over these drug-layered shells to control the drug release. Dissolution study was carried out in 900ml IN HCl apparatus II (paddle) at 50 rpm.

Example 2

Ciprofloxacin hydrochloride was dissolved in aqueous solution of HPMC E5 along with PEG 400 and talc. The coating was carried out in local made coating pan (non- perforated), gun nozzle diameter 0.5mm, atomization air pressure 1.5-2.5 k/cm2, spray rate 1-1.5 /min, bed temperature 35-40⁰C. These coated shells were cured in tray dryer for 24 hours at 40⁰C. Ethocel N 50 and HPMC E5 (85:15), dibutyl phthalate, talc, methylene chloride and isopropyl alcohol were applied over these drug-layered shells to control the drug release. Dissolution study was carried out in 900ml IN HCl apparatus IJ (paddle) at 50 rpm. Fig.3 describes release of drug from these drug-layered substrates.

Example 3

Propranolol hydrochloride was dissolved in aqueous solution of HPMC E5 along with PEG 400 and talc. The coating was carried out in local made coating pan (non- perforated), gun nozzle diameter 0.5mm, atomization air pressure 1.5-2.5 k/cm2, spray rate 1-1.5 /min, bed temperature 35-40°C. These coated shells were cured in tray dryer for 24 hours at 40°C. Eudragit® RSPO and RLPO (65:35), triethyl citrate, talc, acetone and isopropyi alcohol were applied over these drug-layered shells to control the drug release. Dissolution study was carried out in 1000ml IN HCl apparatus II (paddle) at 100 rpm.

Example 4

Propranolol hydrochloride was dissolved in aqueous solution of HPMC E5 along with PE 400 and talc. The coating was carried out in local made coating pan (non- perforated), gun nozzle diameter 0.5mm, atomization air pressure 1.5-2.5 k/cm2, spray rate 1-1.5 /min, bed temperature 35-40⁰C. These coated shells were cured in tray dryer for 24 hours at 4O⁰C. Ethocel N 50 and HPMC E 5 (90:10), triethyl citrate, talc, acetone and isopropyi alcohol were applied over these drug-layered shells to control the drug release. Dissolution study was carried out in 1000ml IN HCl apparatus II (paddle) at 100 rpm. Fig.4 describes release of drug from these substrates.

Drug release in IN HCl for 24hours in modified dissolution apparatus USP XXX dissolution test apparatus II (paddle) was used in the dissolution study. Basket (40#) was placed at the center of the distance between the paddle shaft and wall of the vessel such that media filled into the bottom half of the basket. The upper half of the basket was above the surface of the media. The basket was held in its position by means of a wire whose other end was tied to the vessel. This arrangement was made to simulate floating condition in-vivo. Film coated drug-layered hollow polymeric shells were placed into this basket. The amount of these shells were so chosen that at any point of time all the spheres were in contact with the media and no spheres remained submerged or above the surface of the media.

Results

The dissolution profile of Ciprofloxacin HCl and Propranolol HCl are provided in Fig. 3 and 4. Looking at the profile it gives an impression that further improvement in the formulation was required to control the release rate. However the striking observation was that at the end of dissolution studies not even a single unit was found at the bottom of the basket. When these hollow shells were re-suspended in the media, they remained floating. These hollow polymeric devices should therefore remain floated in the GI tract when ingested.

Claims

I claim

1. A substrate that is partially or completely hollow from inside and capable of floating over water.

2. A substrate as in claim 1, wherein the substrate is made up of water insoluble material.

3. A substrate as in claim 2, wherein the water insoluble material is selected from but not limited to cellulosic polymers, cellulose ether polymers, methacrylate polymers, waxes or combinations thereof

4. A substrate as in claim 1, wherein an active agent is embedded in the substrate wall

5. A substrate as in claim 1, wherein an active agent is layered or coated over the substrate

6. A substrate that is partially or completely hollow from inside and capable of floating over water and comprises at least one of the excipients selected from polymers, waxes or combinations thereof and any other pharmaceutically acceptable excipients

7. A substrate as in claim 6, wherein the acceptable pharmaceutical excipient can be selected from but not limited to plasticizers, water soluble components, detackifiers.

8. A substrate as in claim 7, wherein the plasticizers are selected from but not limited to polyethylene glycol, hydroxypropyl ellulose, hydroxyprpyl methylcellulose, polyvinyl pyrrolidone, triethyl citrate, triacetin.

9. A substrate as in claim 7, wherein in water soluble component is selected from but limited to lactose, mannitol, sugar.

10. A substrate as in claim 7, wherein the detackifier is selected from but not limited to talc, magnesium stearate.

I L A substrate that is partially or completely hollow from inside and capable of floating over water and the process of their preparation include a. coating an inert water soluble material with excipient selected from polymers, waxes or combinations thereof, any suitable pharmaceutical excipient and at least one water soluble pharmaceutically acceptable excipient, b. partial or complete removal of the core material from these coated entities by soaking in water or by any suitable means and drying, c. optionally coating these substrates with a water-insoluble material.

12. A substrate as in claim 1 1, wherein the water soluble core can be selected from sugar, lactose, mannitol, sucrose

13. A substrate as in claim 1 1, wherein the water insoluble material can be selected from polymer or wax or combinations thereof.

14. A substrate as in claim 1 1, optionally the substrate may be coated with an active agent

15. A substrate as in claim 11, wherein the number of unit carrying this active in the final dosage form is at least 1

16. A Substrate as in claim 11, wherein the water soluble excipient in coating is selected from but not limited to lactose, mannitol, sugar, polyvinylpyrrolidone