FORM 3
THE PATENTS ACT, 1970 (39 of 1970)
STATEMENT AND UNDERTAKING UNDER SECTION 8
[See rule 13]

1. We, Wockhardt Limited, Wockhardt Towers, Bandra Kurla Complex, Bandra (East), Mumbai 400 051, an Indian Company registered under the Companies Act 1956 hereby declare:

(i)

that we who have made this application jointly with Wockhardt Limited, Wockhardt Towers, Bandra Kurla Complex, Bandra (East), Mumbai 400 051, an Indian Company registered under the Companies Act 1956, made for the same invention application for patent in the other countries, the particulars of which are given below :

(ii)
(iii)

Country
USA
Date of Filing
25'" May 2001
that the rights in this application(s) has/have been assigned to
Wockhardt Limited
that we undertake that upto the date of acceptance of the complete specification by the controller, we would keep the controller informed in writing the details regarding corresponding applications for patents filed outside India within three months from the date of this application.

Dated this 30th day of August 2001


A S Gosavi Vice President Pharma Research & Regulatory Affairs

To
The Controller of Patents,
The Patents Office Branch, Mumbai.


PATENT
IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
Applicant: Vinay K. Sharrna et al. Examiner: Unknown
Serial No.: Unknown Group Art Unit: Unknown
Filed: Herewith Docket: 535.033US1
Title: RATE-CONTROLLED DELIVERY OF PHARMACEUTICAL COMPOSITIONS
INFORMATION DISCLOSURE STATEMENT
Assistant Commissioner for Patents Washington, D.C. 20231
In compliance with the duty imposed by 37 C.F.R. § 1.56, and in accordance with 37 C.F.R. §§ 1.97 et. seq., the enclosed materials are brought to the attention of the Examiner for consideration in connection with the above-identified patent application. Applicants respectfully request that this Information Disclosure Statement be entered and the documents listed on the attached Form 1449 be considered by the Examiner and made of record. Pursuant to the provisions of MPEP 609, Applicants further request that a copy of the 1449 form, initialled by the Examiner to indicate that all listed citations have been considered, be returned with the next official communication.
Under 37 C.F.R. § 1.97(b)(3), it is believed that no fee or certificate is required with this Information Disclosure Statement However, if an Office Action on the merits has been mailed, the Commissioner is hereby authorized to charge any additional fees or credit any overpayment to Account No. 19-0743.
The Examiner is invited to contact the Applicants' Representative at the below-listed telephone number if there are any questions regarding this communication.
Respectfully submitted, VINAY K. SHARMA ET AL. By their Representatives,
SCHWEGMAN, LUNDBERG, WOESSNER & KLUTH, P.A.
P.O. Box 2938
Minneapolis, MN 55402
(612) 373-6968 w

"Express Mail" mailing label number; EL 721294732 US
Date of Deposit: May 25. 2001
This paper or fee is being deposited 04 the date indicated above with the United States Postal Service pursuant to 37 CFR
1.10, and is addressed to the Commissioner for Patents, Box Patent Application, Washington, D.C. 20231.

Sheet 1 of 1
Form 1449* Atty. Docket No.: 535.033US1 Serial No. Unknown
INFORMATION DISCLOSURE STATEMENT Applicant: Vinay K. Sharma et al.
BY APPLICANT (Use several sheets if necessary') Filing Date: Herewith Group: Unknown
U.S. PATENT DOCUMENTS

* Examiner Initial

Document Number

riling Oat* If approprlata

4,816, 5,073, 5,100, 5,314, 5,451, 5,656, 5,658, 5,681, 5,697, 5,733, 5,756, 5,776, 5,780, 5,824, 5,849, 5,871, 5,877, 5,885, 5,916, 5,922, 5,945, 5,997, 6,039,

264 380 675 697 409 291 589 582 922 568 123 501 057 341 329 776 175 615 592 352 125 906 976

03/28/1989 12/17/1991 03/31/1992 05/24/1994 09/19/1995 08/12/1997 08/19/1997 10/28/1997 12/16/1997 03/31/1998 05/26/1998 07/07/1998 07/14/1998 10/20/1998 12/15/1998 02/16/1999 03/02/1999 03/23/1999 06/29/1999 07/13/1999 08/31/1999 12/07/1999 03/21/2000

Phillips, R., et al. Babu, S.R., et al. Cho, W.P., et al. Kwan, H.K., et al. Rencher, W.F., et al. Olsson, B., et al. Parekh, K.B., et al. Gilis, P.M., et al. Thotnbre, A. G. Ford, L.C.
Yamamoto, T., et al. Kokubo, H., et al. Conte, U., et al. Seth, P., et al. Conte, U., et al. Mehta, A.M. Sargent, B.J., et al. Chouinard, F., et al, Parekh, K.B., et al. Chen, C, et al. Kim, C.
Wood, T.G., et al. Mehra, D.K., et al.

424 468
424 472
424 468
424 480
424 468
424 458
424 463
424 468
604 892
424 433
424 451
424 494
424 468
424 473
424 469
424 462
514 252
424 465
424 464
424 465
424 473
424 494
424 480

06/06/86 07/09/90 11/13/90 10/23/92 11/22/93 04/21/95 10/31/91 06/07/94 10/13/93 06/02/95 02/07/97 11/07/95 02/14/97 08/11/95 09/07/95 10/28/96 03/26/96 08/19/96 02/18/97 01/31/97 06/21/96 11/13/97 11/26/97

Porn—nt Injmber

FOREIGN PATENT DOCUMENTS
Country

Translation ias I Ho

Initial

OTHER DOCUMENTS
(Including Author, Title, Date. Pertinent Pages, Etc.)

Examiner

Date Considered

•Substitute Disclosure Statement Forn (PTO-1449)
"EXAHIMES.I Initial if citation considered, whether or not citation is in conformance with HPEP £09,- Draw line through citation if not in conformance and not considered. Include copy of this form with next communication to applicant.

Docket #535.033US1
RATE- CONTROLLED DELIVERY OF PHARMACEUTICAL
5 COMPOSITIONS
Cross-Reference to Related Application
This application claims priority of U.S. provisional patent applications Serial No. 60/240,913 filed May 26,2000, which is incorporated herein by reference.
10
Background of the Invention Pharmaceutical formulations for oral administration are often prepared as a type of core such as, for example, small particles such as beads or pellets or into tablets. Often these cores and tablets will incorporate a coating.
15 It is known to provide a polymer matrix for sustained release of a water-
soluble drug. For example, U.S. Patent No. 5,314,697 describes a matrix composed of a high viscosity hydroxypropyl methyl cellulose 2208, U.S.P. (Methocel* K100 M, 100,000 cps, 2% w/w dispersion in water), and a low viscosity ethyl cellulose (Ethocel®, 9 cps) in 4:1 combination with povidone (as a secondary binder),
20 dicalcium phosphate as an excipient for compression, a glidant and a lubricant. The core has a coating composed of a low viscosity hydroxypropyl methyl cellulose 2910, U.S.P. (Methocel* E-5,5-6 cps), plasticized with polyethylene glycol 400 and 3350 as material for a loratadine-containing film coating. According to this patent, an extended release formulation of loratadine/pseudoephedrine can be prepared.
25 U.S. Patent No. 4,816,264 discloses a composition having pseudoephedrine
in a hydroxyethyl cellulose matrix having a viscosity of from about 90 to about 4000 cps and a semipermeable coating that includes a methacrylate ester surrounding the core. U.S. Patent No. 5,073,380 discloses a slow release composition for active agents wherein the composition has a core including two
30 polymers, hydroxyethyl cellulose and povidone, a wicking agent and erosion
1


polymer, as well as an additional amount of an enhancer. U.S. Patent No. 5,451,409 also describes a pharmaceutical sustained release matrix and oral dosage form comprising a homogeneous matrix containing an effective amount of a medicament and a polymer blend of hydroxypropyl cellulose and hydroxyethyl cellulose. U.S.
5 Patent No. 5,100,675 discloses a sustained release dosage form of ibuprofen and pseudoephedrine having loratadine in a coating for immediate release.
The coating of pharmaceutical cores or matrices is also conducted for aesthetic or functional reasons. Aesthetic coatings are normally achieved using water-soluble, low viscosity film forming polymers such as hydroxypropyl methyl
10 cellulose, methyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, and sodium carboxymethyl cellulose. In addition, it is known to apply a film coating or membrane coat to a tablet core. See, e.g., U.S. Patent Nos. 5,100,675; 5,314,697 (discussed above); or U.S. Patent 5,681,582; 5,780,057; and 6,039,976, which describe film various types of coatings.
15 Functional coatings achieved with aqueous polymeric membranes that are
often used to create modified dosage forms. These functional coatings generally are usually composed of pseudo-latex emulsions of ethyl cellulose, colloidal dispersions of poly(meth)acrylates or silicone elastomer latex dispersions.
The coating techniques require that the cores have sufficient strength to
20 withstand the physical stress that pharmaceutical formulations undergo during manufacture. Such stresses can include, for example, rolling and frictional processes in the pan and impact stress during formulating to which the compositions are exposed in fluid-bed equipment. Film coatings applied to substrates, however, require harder, more abrasion-resistant substrates that are less susceptible to impact
25 stress because the formation of a coherent film coating takes substantial time during the manufacturing process. Typically, the cores are exposed to frictional forces, impact forces and pressure as a result of rolling or fluidization.
Resistance to water in the film coating is also required to prevent swelling and softening of the surfaces under the influence of ambient moisture, especially at
30 the start of the coating process. If the granule moisture of the compressed tablet is
2

higher than the optimum, e.g., about 3.5 %, the cores tend to weaken in structure on exposure to high temperature during the subsequent film coating operation. This behavior is attributed to the release of entrapped moisture that develops a high vapor pressure within the tablet on heating.
5 Another factor that affects film coatings on pharmaceutical products is the
presence of a hydrophilic swelling substance in the core. A hydrophilic swelling substance is typically incorporated as a disintegrant that causes the core to swell under the influence of moisture. Stresses due to volume changes (e.g., swelling of a tablet or a component within a tablet during storage at high humidity) can be a
10 serious problem that often requires reformulation of the tablet core. The
reformulation of a product due to the inability of a film coating to adapt to a change in conditions, such as humidity variations during shipping or storage is undesirable. In addition, during the coating process, the risk of water vapor penetration of the core is low, as long as the coating is dried quickly during the manufacturing process.
15 However, in humid, uncontrolled environments, the risk of moisture absorption by the core increases, along with complications of evaporation and internal pressure generation.
Acrylic film coatings initially swell due to hydration of the matrix until eventually the swelling forces within the tablet split the film coating. Semi-
20 permeable film coatings containing ethyl cellulose (e.g., Surelease® by Colorcon, USA) will significantly and unreliably slow down drug release from heterogeneous swellable matrix ("HSM") tablets, especially at lower weight gains of 1-3 percent based on the weight of the HSM tablets.
If there is a significant difference between the thermal expansion coefficients
25 of the coating and the substrate, stress can be created during the coating process due to temperature changes that occur.
The type of filler used can affect the thermal expansion of a tablet core. The organic fillers have thermal expansion values comparable to those of polymeric film forming polymers. The inorganic tablet fillers have very low thermal expansion
30 values. Thus, the incidence of tablet core cracking tends to be related to the amount

of organic fillers in the cores. Tablet core formulations are also known to swell
upon storage, specifically at high ambient relative humidity. See S.A. Sangekar et
al., "Effect of Moisture on Physical Characteristics of Tablets Prepared from Direct
Compression Excipients" 61 J. Pharm. Sci. 939 (1972).
5 The defects reported in aqueous film coated tablets can generally be divided
into three groups depending on the complexity of the solution:
Group 1: defects such as blistering (wrinkling), chipping,
cratering, picking, and pitting;
Group 2: defects such as blooming, blushing, color variation,
10 infilling, mottling, and orange peel (roughness);
Group 3: bridging, cracking, flashing, peeling, splitting-defects associated with high internal stresses within the film coating. It has been also indicated that by increasing the molecular weight of the 15 polymer, cracking of coated films is stopped. R.C. Rowe and S.F. Forse, "The Effect of Polymer Molecular Weight on the Incidence of Film Cracking and Splitting on Film Coated Tablets," 61 J. Pharm. Sci. 939 (1972). In another report, a group of investigators employed Eudragit© RL 30D and Eudragit© NE 30D in a 70:30 ratio. A binary film of two poly(meth)acrylates reportedly performed as a 20 functional membrane which was mechanically strong and resilient. See A.A.
Deshpande et al. "Development of a Novel Controlled-Release System for Gastric Retention", 14(6) Pharm. Res. 815-819 (1997).
The strength/mechanical properties of the polymers employed in a core coating will determine the incidence of various defects. Low molecular weight 25 polymers tend to be weak, however, as the molecular weight of the polymer is increased, the mechanical properties also increase. It is also known that blending high and low molecular weight grades of a polymer can increase a film's effective strength. Plasticizers are often employed to decrease internal stress in a polymer film or membrane coating.

Applicants' efforts have addressed unfulfilled needs for a membrane or film coating that is resilientiy expandable to remain intact despite stresses such as swelling of a core and that can contain a drug for rapid release.
5 Summary of the Invention
The present invention provides a pharmaceutical composition of an active agent in a swellable sustained release delivery matrix. The matrix includes a hydroxy ethyl cellulose having a viscosity of from about 4500 to about 6500 cps at 2% by weight in water, an excipient material selected from the group consisting of
10 dicalcium phosphate, a cyclodextrin, and mixtures thereof; and a binder.
The invention also includes a pharmaceutical compositions comprising a swellable matrix wherein the matrix is surrounded by a water dispersible membrane comprising a low viscosity hydroxyethyl cellulose substituted with hydroxyethoxy groups; and hydroxyalkyl cellulose optionally substituted with methoxy groups or
15 hydroxyalkyl cellulose substituted with ethoxy groups and a plasticizer, and a
process for preparing the coated compositions. The water dispersible membrane can also include an active agent that is the same or different from the active agent in the core.
Examples of active agents (drugs) useful for preparing cores of the present
20 invention include insoluble drugs such as, for example, felodipine and soluble active agents such as, for example, pseudoephedrine, diltiazem and phannaceutically acceptable salts thereof.
Examples of active agents (drugs) useful for preparation of a drug containing water dispersible membrane of the present invention include insoluble active agents
25 such as, for example, loratadine, descarboethoxy loratadine, tamoxifen, enalapril maleate and astemizole and soluble active agents such as, for example, captopril and the like.

30

Brief Description of the Figures

Figure 1 is an illustration of a tablet with a film coating produced when a core matrix is coated with an aesthetic membrane comprised of an hydroxypropyl methyl cellulose (HPMC) based formulation (traded as Opadry® by Colorcon, USA);
5 Figure 2 is an illustration of a tablet of Figure 1, with a ruptured film after
the film was exposed to 40°C/75% relative humidity;
Figure 3 is an illustration of a tablet with a film coating produced according to the present invention after exposure to 40°C/75% relative humidity. The improved film integrity was attained by applying a resilient film coating comprised 10 of a low viscosity hydroxyethyl cellulose suitably plasticized with polyethylene glycol
Figure 4 is an illustration of a tablet with a film coating produced according to the present invention after exposure to 40°C/75% relative humidity. The improved film in this Figure was prepared using a resilient film coating of 15 plasticized low viscosity hydroxyethyl cellulose and hydroxypropyl methyl cellulose (7:3 ratio by weight). This was prepared using significantly shorter coating times.
Figure 5 is an illustration of a tablet with a film coating produced according to the present invention using a film of the type shown in Figure 4, which includes a 20 drug and applied on a swellable matrix.
Figure 6 is an illustration of a tablet with a film coating produced according to the present invention using a film of the type shown in Figure 4, which includes a drug and P-cyclodextrin and applied on a swellable matrix;
Figure 7 is an illustration of a tablet with a film coating produced according 25 to the present invention using a film of the type shown in Figure 4, which includes descarboethoxy loratadine, P-cyclodextrin, and hydroxy carboxylic acid, and applied on a swellable matrix; and
Figure 8 is an illustration of a tablet with a film coating produced according to the present invention using a film of the type shown in Figure 4, which includes

enalapril maleate/p-Cyclodextrin/magnesium trisilicate-loaded and applied on a swellable matrix.
Figure 9 illustrates the particle diameters of loratadine prior to and after
micro fluidization;
5 Figure 10 is an illustration of a tablet with a film coating produced according
to the present invention using a film of the type shown in Figure 4, which includes loratadine in the film and pseudoephedrine in the core.
Figure 11 illustrates a comparison of the percentage of pseudoephedrine sulfate released from a formulation of the invention to and a dosage form of a 10 commercially available product, Claritin®.
Figure 12 illustrates the percentage of loratadine released from a formulation of tho invention and a dosage form of a commercially available product, Claritin®.
Detailed Description of the Invention
15 The present invention is directed to a composition comprising a swellable
polymer matrix core containing an active agent (drug) for delayed or extended release. The invention also provides a resilient polymer membrane coating for the cores, which optionally contains an active agent (drug). The drug in the coating can be the same or different from the drug in the core.
20 Thus, in one aspect, the present invention relates to a two-component drug
delivery system, such as, for example, a core/tablet, including a rapid-release drug-loaded polymer film coating and a controlled release core. In another aspect, the present invention relates to a single component drug delivery system, such as, for example, a tablet, including polymer film coating and a controlled release core. The
25 polymer coating of the invention is elastic in nature. Thus, it can serve as a drug delivery device, and also surrounds the core matrix with an elastic membrane, which prevents formation of surface cracks caused by internally created swelling-related stress.
An advantage of the matrix core of the present invention is its controlled
30 swelling/erosion. The matrix includes a combination of medium viscosity

hydroxyethyl cellulose ("HEC"), and an excipient such as, for example, dicalcium phosphate dihydrate ("DCP"), a cyclodextrin such as P-cyclodextrin ("P-CD") or a mixture thereof, and optionally a binder.
It is believed that the following steps represent the physical model of the 5 release of a drug from HEC:
a.) diffusion of water into the polymer matrix leading to an
initiation of drug release through the diffusion front,
b.) instantaneous swelling of the matrix leading to an immediate
control of the release of the pharmacologically active agent.
10 c.) formation of a viscous, erosion rate-controlled drug delivery
system, d.) geometric (shape and size) controls of matrix erosion and hence rates of drug release. Specific active agents include useful for practicing the invention include 15 non-steroidal anti-inflammatory drugs (NSAIDS) such as, for example, naproxen sodium, diclofenac, sulindac, oxaprozin, diflunisal, aspirin, piroxicam, indomethacin, etodolac, ibuprofen, fenoprofen, ketoprofen, mefenamic acid, nabumetone, tolmetin sodium, ketorolac tromethamine and the like;. Preferred NSAIDs are etodolac, and ibuprofen; histamine receptor antagonists 20 (antihistamines) such as, for example, loratadine, descarboethoxy loratadine,
astemizole and the like; such as, for example, tamoxifen and the like; angiotensin converting enzyme (ACE) inhibitors such as, for example, enalapril and the like; calcium channel blockers (calcium antagonists), such as, for example, felodipine, diltiazem, nifedipine and the like; and bronchodilators such as, for example, 25 pseudoephedrine and the like. Preferred combinations of active agent combinations include diltiazem cores with enalapril in a film coating, felodipine cores with enalapril in a film coating and pseudoephedrine cores and enalapril, loratadine, descarboethoxy loratadine, or astemizole in a film coating. The preferred active agent combination is pseudoephedrine in the core and loratadine in a film coating.

Examples of excipients useful for practicing the present invention include insoluble alkaline components such as dicalcium phosphate dihydrate ("DCP"), hydroxycarboxylic acids such as, for example, citric acid, tartaric acid, ascorbic acid, gluconic acid, malic acid, lactic acid, treonic acid and the like; cyclodextrins
5 and mixtures thereof.
The cyclodextrins useful in the present invention include but are not limited to o-cyclodextrin, P-cyclodextrin, Y-cyclodextrin, dimethyl - P-cyclodextrin and hydroxyethyl - P-cyclodextrin. The preferred cyclodextrin is P-cyclodextrin.
The hydroxycarboxylic acids useful in the present invention include but are
10 not limited to citric acid, tartaric acid, ascorbic acid, gluconic acid, malic acid, lactic acid, treonic acid and the like. The preferred hydroxycarboxylic acids are citric acid, tartaric acid, and malic acid. The most preferred hydroxycarboxylic acid is citric acid.
The amount of excipients useful in the compositions of the invention is from
15 about 50 to about 80 weight percent of the composition based on the total weight of the composition. Preferably the amount of excipients is from about 60 % to about 75%. The most preferred amount of excipients is from about 60 to about 70 weight percent of the composition based on the total weight of the composition.
DCP is included as an excipient. The particle size distribution of this
20 material can range from very fine to coarse. A preferred material, e.g., has a particle size distribution of from about 74 u.m (not more than 15% passes through a # 200 screen) to about 425 um (not more than about 5% retained on a # 40 screen). This material is available as Emcompress* from Edward Mandell, USA.
Drugs that are very soluble in water will tend to absorb more water and
25 provide a high equilibrium moisture content. This is believed to cause a greater swelling of the matrix. For example, when a (shaped) core matrix prepared with pseudoephedrine sulfate and a medium viscosity grade of HEC in a ratio of 1:1.5, the cores split along the major axis of the ellipsoid, when coated with HPMC (Opadry® Clear). However, when an insoluble drug, nifedipine was prepared in a
30 similar shaped matrix composed of the same medium viscosity HEC and two

hydrophilic excipients such as P-cyclodextrin and DCP, neither film rupture nor core splitting is observed when coated with HPMC (Opadry® Clear). This result was attributed to the deformation of the core matrix. When a low dose hydrophobic drug is compressed in the presence of the same polymer and excipient mixture,
5 without DCP (due to reasons ofincompatibility) a film rupture was observed. See Figure 2. This result was attributed to elastic recovery of the core matrix containing P-cyclodextrin as the excipient.
In the matrix of the invention, as the HEC polymer used in the matrix undergoes resilient deformation, suitable excipients such as P-cyclodextrin and DCP
10 are provided to develop a pseudo-plastic core that resists friability during the film coating process.
HEC polymer viscosities correspond appropriately with their respective performances. Low viscosity polymer performs in a time-controlled or rapid release manner whereas medium viscosity polymers perform in a rate-controlled manner.
15 HEC is commercially available, for example, in a viscosity of 75-150 cps,
e.g., Natrosol 250 L Pharm., 5% w/w in water, a viscosity of 4500-6500 cps, e.g., Natrosol 250 M Pharm., 2% w/w water; a viscosity of 1500-2500 cps, e.g., (Natrosol 250 H Pharm, 1% w/w in water. The molecular weight distribution ranges from about 90,000 (grade L) to about 1,000,000 (grade H). A preferred HEC for the
20 matrix of the invention is Natrosol 250 M having a viscosity of 4500-6500 cps, 2% w/w water (traded by Aqualon, Wilmington, Delaware). A preferred range of HEC is from about 10 to about 50% w/w of HEC, based on the total weight of the core. A more preferred range of HEC is from about 15 to about 40% w/w. The most preferred range of HEC is from about 20 to about 30% w/w.
25 A resilient membrane can improve the physical integrity of swellable
matrices that are internally stressed due to the viscoelasticity of the matrix-forming polymer. The membrane protects the matrix from rupture by forming a resilient membrane around the matrix. The resiliency of the membrane is attributed to a combination of tensile strength and elongation under stress.

As mentioned, the coating of pharmaceutical matrices with a membrane is traditionally carried out for aesthetic or functional objectives. If a matrix is intentionally designed to be highly swellable for erosion-controlled drug delivery, a film for aesthetic coating requires an optimum adhesion to the substrate and
5 resiliency of the coating membrane for achieving acceptable product appearance. This is accomplished by diffusing stresses created within the film structure as well as in the core matrix and is achieved by combining low viscosity HPMC and HEC. Low viscosity grades of HEC along with HPMC, both suitably plasticized, provide optimum tensile strength and elongation under stress.
10 Non-limiting examples of plasticizers useful for the present invention are
materials such as triethyl citrate, triacetin, propylene glycol, glycerol monostearate, polyethylene glycol, and the like. A preferred plasticizer is polyethylene glycol 400.
Thus, in another aspect, the present invention provides a resilient film coating for a tablet, which may contain a drug therein for rapid release. The film
15 coating comprises of a low viscosity HEC, NF (e.g., Natrosol® 250L from Aqualon Division of Hercules, Delaware, USA, or Cellosize® HEC QP-40 by Amerchol, USA. A 2% w/v aqueous dispersion provided a viscosity of 80-125 cps in both cases).
In another aspect of the present invention, the film coating can serve as a
20 rapid or immediate release conduit for a variety of active agents including, but not limited to, hydrophilized low dose hydrophobic drugs, water-soluble drugs for providing a loading dose, and peptidic drugs for early absorption at the gastro-duodenal junction. Hydrophilization of discrete particles is achieved by bringing the hydrophobic active agent particles and a hydrophilizing agent such as, for example,
25 a cyclodextrin to close proximity, through a process such as microfluidization or wet micronization. An application-based approach includes pulsatile delivery of low dose proton pump inhibitors deposited on swellable delivery systems of macrolide antibiotics. The film may also serve as a transport vehicle for absorption enhancers required for permeability-challenged molecules and for enzymatic inhibitors to
30 suppress metabolic degradation of drugs, which undergo intestinal metabolism. .

When HSMs of drugs such as non-steroidal anti-inflammatory drugs (NSAID), antihypertensives, and decongestants (representing hydrophobic and water-soluble properties) are coated with traditional coating materials such as HPMC (traded as Opadry® by Colorcon, USA), small cracks in the coating were
5 noticed after approximately half the film coating dispersion was applied to the tablet cores. It is observed that the cracks appeared in 30-40% of the tablets. Once formed the cracks eventually worsen and manifest large areas where the film coating actually peeled off the tablets. The processing conditions during this coating are well within specifications for the Opadry® coating. Initially, causes of the coating
10 cracking are believed to be caused by: (1) materials lacking sufficient mechanical strength or adhesive properties; (2) the tablet face may be soft; and (3) the tablet shape and how it may slides along its face in a coating pan.
Another finding is related to the composition of the HSM core. For example, the cracking of an Opadry® based film and the splitting of the core is
15 believed to be related to various heterogeneous swellable matrix core factors such as granule moisture, excipient type, drug solubility and concentration, concentration of the swellable polymer, deformation of the HSM, physical characteristics of the matrix influenced by compression, proportions of drug to polymer to excipient, and the shape and size of the matrix.
20 Based on the above-described model of Rowe and Forse for creation of
internal stresses within the film, it was observed in the current invention that an HPMC-based film has better adhesion than cohesion, whereas a Natrosol® 250L-based film had better cohesion than adhesion. These is illustrated in Figure 1, where felodipine extended release tablets are coated with Opadry® only (customized
25 Methocel® E5 formulation traded by Colorcon, USA). On the other hand, the tablet illustrated in Figure 3, does not develop internal stresses within the film because the cohesion is better due to high molecular weight (90,000 in Natrosol® 250L vs. 12,000 in Methocel® E-5), however adhesion is poor due to the lack of Methocel® E-5.

Low viscosity HPMC films are considered a standard in the pharmaceutical industry from the standpoint of film coating for aesthetic purposes. As the required viscosity of a solution for aqueous film coating is commonly less than 100 cps, the maximum concentrations of 3, 6 and 15 cps grades which can be used in film
5 coating are therefore contain approximately 14, 7.5 and 4.5% of HPMC,
respectively. Commercially, Pharmacoat® 603, 606 and 615 represent materials with these viscosities and percentages of HPMC. The tensile strength (OR) and elongation (ER) for these three Pharmacoat© materials is 48/3.3, 56/22.6 and 67/23, respectively.
10 HPMC has a very high tensile strength but a very low degree of elongation.
In other words, it is a strong film but has no flexibility or elasticity. These properties may be increased by adding plasticizefs. However, the value of increasing the level of plasticizer is limited in its performance because there usually is an optimum level of plasticizer. Further, a plasticized film such as Opadry® does
15 not provide sufficient flexibility for coating swellable cores.
The tensile strength of HPMC (E5 grade based commercial Opadry® product) is inadequate to protect the physical integrity of internally stressed HSMs when exposed to high temperature and humidity (40°C/75% RH). These matrices cracked under this pressure due to significant though controlled swelling. See, e.g.,
20 Figure 2.
Another parameter, as the glass transition temperature (Tg), the temperature of a polymer below which it exists in a glass state, is characterized by a sub¬structure in which there is minimal polymer chain movement. For example, the Tg value for HPMC (Methocel®, E-grade, 6 cps) is 170-180°C. An approximate value
25 for HEC is 125°C based on its melting point of 135-140°C. Pure ethyl cellulose has a Tg of 129°C. Lower values of Tg are preferred for flexibility and elasticity because optimum polymer chain movement and hence flexibility to the film is achieved.
It has been discovered that, based on the mechanical properties of HEC, a coating formulation could be developed which might behave differently than
30 HPMC-based films (which are strong but have poor elongation (resiliency)). In a

cold extrusion study it was discovered that HEC is highly elastic compared to HPMC. Thus, it was postulated that HEC films, for equivalent grades of molecular weights and viscosities, might provide higher elongation (eR at break. The elongation at break with a film formed from HEC is superior to a similar film
5 formed from HPMC.
CM-type HEC such as CM-L4 represents low viscosity (14 cps) grades of HEC. Plasticizer, e.g., commercially available, pharmaceutically acceptable plasticizers for polymers, such as compositions containing polyoxyalkylene chains, such as polyoxyethylene or poly(oxyethylene/oxypropylene) chains, such as glycols
10 or glycol-containing plasticizers such as polyethylene glycol ("PEG") 400 were found to be beneficial in providing a contiguous and membrane coating.
When an HSM prepared according to the present invention is coated with a 7.5% w/w aqueous dispersion of HEC, (100-125 cps's, traded as Natrosol© 250L), plasticized with 10% polyethylene glycol 400, w/w based on the dry polymer
15 weight, the film stretches with the expansion of the heterogeneous swellable matrix and assumes the shape of the matrix. Further, no retardation in drug release was observed.
The membrane coating process was also improved by blending Natrosol® 250 L with low viscosity Opadry® Clear to shorten spraying time by increasing the
20 solids content of the dispersion. The film becomes less hygroscopic because HPMC is less hygroscopic compared to the 250L grade of HEC. The hygroscopicity of 250 L-based film is due to the high degree of substitution (2.5; maximum substitution is 3.0) with hydroxyethoxy groups which increase solubility.
Other HEC compositions suitable for use in the present invention are
25 available from Fuji Chemical Co., Osaka, Japan. These compositions include water-soluble gel-forming agents known as CM-type HECs, which include from about 30 to about 50% substituted hydroxyethoxy groups in the cellulose and has a viscosity of from about 14 to about 1280 cps in a 2% by weight water solution.
Thus, a preferred resilient membrane according to the present invention
30 includes low viscosity hydroxyethyl cellulose (80-125 cps) suitably plasticized with

a plasticizer such as polyethylene glycol 400 and optionally including a blend of low viscosity HPMC polymers (preferably 5 cps's and 50 cps's, also suitably plasticized). A suitable blend of HPMC polymers (5 cps's and 50 cps's) plasticized with polyethylene glycol is traded as Opadry® YS-3-7065 by Colorcon, USA. Separately, these plasticized polymers do not provide a resilient coating to the swellable matrices of loratadine/pseudoephedrine sulfate. However, when these individually prepared formulations of polymers are blended in a suitable ratio (HEC/HPMC), the coating is exceptionally resilient on exposure to heat and humidity. It is preferred that the HECHPMC ratio is about 1:1 to about 3:1, more preferably, about 7:3 or 6:4.
Another batch formulation having an initial hardness of greater than 125 N and a loss on drying ("LOD") of 1.5-2% was prepared. The tablets were coated with a base coating (sub-coating) of Natrosol® 250L (7.5% solids content). As HEC was highly hygroscopic and relatively more cohesive than adhesive, the coating time was lengthened to about 3 hours. It is observed that even though there was no film rupture, slight pitting was observed near the letter W. Figure 3 illustrates a relatively poor film integrity attained by applying a base coating of Natrosol® 250L, formed as a result of poor adhesion. The adhesion of the film coating was improved by blending Opadry® Clear with Natrosol® 250 L to achieve an optimum coating time of about 40 minutes and a superior product finish. See e.g., Figure 4: an optimum film integrity was attained by applying a base coating of Natrosol® 250L:Opadry® in a 60:40 proportion.
An optimum moisture level in the core matrix of the current invention was determined to be less than about 3%, preferably less than about 2.5%, and more preferably less than about 2%. When granule moisture LOD was more than 3.5%, tablet softening was observed during application of high inlet temperature (>70°C) at an inlet air humidity of 70%. A development of high vapor pressure within the tablet prepared with more than 3.5% LOD of granules led to the softening of the tablet, even though the initial hardness was 125 N. However, when the tablet structure was created at lower granule moisture and an initial hardness of only 70N

(due to overdrying) at the same inlet air humidity, coating was continued successfully. See, e.g., Figure 1. However, as the tablets were coated with Opadry©-based coating dispersion, cracking of the film due to internal stresses in the film and splitting of the edges due to an internally stressed, highly swellable matrix.
5 See, e.g., Figure 2.
The invention also uses a process known as "Microfluidization" for blending the active agents in the coating material. The process is described in co-pending U.S. Patent Application Serial No. 09/340,917, filed June 28,1999, titled "Preparation of Micron-Size Pharmaceutical Particles by Microfluidization," which
10 is incorporated herein by reference. The application describes a process where micronized feed materials are microfluidized at low pressures (e.g., about 3,500 to 7,000 or 4,000 to 6,000 pounds per square inch) to effectively prepare particles in the 6-12 micron size range, using from 1-3 passes through a MH-210EA Micro fluidizer.
15 The film may also serve the purpose of acting as a conduit for pulsatile
release of hydrophobic drugs such as loratadine by hydrophilization and for certain peptidic drugs such as captopril and P-lactam antibiotics for early absorption at the gastroduodenal segment of the GI tract. Additionally, the binary film may include absorption enhancers such as taurocholates, sodium taurodeoxycholate,
20 acrylcamitines such as lauryolcarnitine, myristoylcamitine and palmitoylcamitine for prior treatment of a certain section of the lower intestinal tract for enhanced permeability of peptide pharmaceutical agents. Basic alkaline materials such as magnesium trisilicate may be included by microfluidization along with the components of the binary film for stabilizing the pulsatile release component
25 enalapril maleate as in case of fixed combination dosage form of enalapril and controlled release felodipine.
Other than the use of cosolvents, microemulsion dosage forms, pH adjustment for ionizable drugs, and experimental dosage forms such as microparticulates and liposomes, few new viable formation options have been made
30 available to address the problem associated with administering sparingly water

soluble drugs in membrane coatings to achieve optimum biological activity. For example, a drug (active agent) loaded film coating according to the present invention can be provided with microfluidized loratadine for immediate release (i.e. within one hour) upon oral administration of a tablet. By microfluidization, a
5 narrow targeted drug particle size is achieved, in addition to non-agglomeration, and hydrophilization.
Applicants have discovered that an active agent can be incorporated in the membrane coating with favorable results. Accordingly, the membrane coating can provide the mechanical advantages described herein in addition to providing an
10 immediate drug release structure. Thus, rapid drug release of a sparingly soluble drug can be achieved without being hindered by the HEC/HPMC composition of the membrane. Preferred loratadine particle size ranges ire from about 2 to about 50 um, more preferably from about 10 to about 40 um particularly from about 20 to about 30 u.m. Ninety percent of the particles should be within a given range. See,
15 e.g., Example 10, below.
Excipients such as hydroxycarboxylic acids, and insoluble alkaline components are used with low dose drugs for the formation of water soluble inclusion-complexes with cyclodextrins (CD's), enhancement of solubility of cyclodextrins by hydroxycarboxylic acids for amino-type drug-hydroxycarboxylic-
20 cyclodextrin multicomponent complexes (thereby significantly reducing the amount of CD necessary to form inclusion-complexes), or by stabilizing drugs by providing micro-environment of high pH. Examples of these functional excipients are not limited to these three categories.
The increase in oral bioavailability of a drug in a cyclodextrin-containing
25 formulation is believed to be predominantly a result of an increases in the apparent solubility of the drug. As P-CD has a limited water solubility of 18.6 mg/ml or 16.4 mM, a hypothetical drug with an aqueous solubility of 10 ug/ml and a 1:1 binding constant with P-CD of 1 X 104 M-l would have a maximum obtainable solubility of 1.3 mg/ml in the presence of 16.4 mM β-CD. In addition, β-CD often forms B-type

phase-solubility diagrams where the complexes themselves have limited aqueous solubility.
Tamoxifen citrate (equilibrium solubility in water 37° is 0.5 mg/ml), a low dose non-steroidal anti-estrogen indicated for breast carcinoma currently available in
5 the form of 10 and 20 mg tamoxifen equivalent doses, has demonstrated solubility enhancement as a hydroxycarboxylic multicomponent complex. It is a candidate for including in the form of a membrane delivery system.
A pharmaceutically acceptable binder can be used in manufacture to prepare a mass of suitable consistency, which after drying will retain its structure until
10 compressed. Pharmaceutically acceptable binders include natural and synthetic adhesives such as, by way of non-limiting examples, sodium alginate, soluble cellulosic materials such as sodium carboxymethyl cellulose, methyl cellulose, and hydroxypropyl cellulose ("HPC"), polyvinyl pyrrolidone and the like. All dissolve in water to give clear, viscous preparations. A preferred binder is HPC and a
15 preferred amount of HPC is from about 3 to about 10 % w/w in water. HPC is commercially available from Hercules as KLUCEL® from Nippon Soda as NISSO HPC®.
Unless otherwise stated, all percentages, parts, ratios, etc., are by weight. Unless otherwise stated, a reference to a compound or component includes
20 the compound or component by itself, as well as in combination with other compounds or components, such as mixtures of compounds. Further, when an amount, concentration, or other value or parameter, is given as a list of upper preferable values and lower preferable values, this is to be understood as specifically disclosing all ranges formed from any pair of an upper preferred value and a lower
25 preferred value, regardless whether ranges are separately disclosed.
A tablet shape is selected to reduce stress gradients within the tablet. With deep oval punches, the larger quantity of material in the dome expands radially during ejection, and as the main body of the tablet cannot expand radially, but is constrained by the die wall, large shear stresses develop. Flat-faced punches would
30 form tablets that avoid this large shear stress, however, it was observed that flat-

faced oval tablets are not suitable candidates for packaging into bottles as they do not roll properly in the "slats" component of the packaging machine. A shallow or standard oval shape is more suitable from various operational angles.
The density, porosity, hardness, and tensile strength of the heterogeneous
5 swellable matrix ("HSM") is dependent on applied pressure. HSM drug delivery
systems in all probability will be non-homogeneous in relation to these
characteristics which will influence the tensile strength of a polymeric film. Hence,
the invention provides a resilient binary HEC/HPMC film useful to contain and
HSM drug delivery system.
10 The invention will now be illustrated by the following non-limiting
Examples.
Examples 1-4 Procedure for Manufacturing the Heterogeneous Swellable Cores Containing an Active Agent
15 Example 1
Heterogeneous Swellable Matrices (HSM) of Pseudoephedrine Sulphate
1. Into a stainless steel container equipped with a magnetic stirrer is added
1200 g purified water. Add 90 g HPC, NF, EP, JP (Klucel LF) under stirring until a
uniform dispersion is formed.
20 2. Charge 720 g of pseudoephedrine sulphate, 450 g DCP, 300 g
unmicronized P-CD, 1080 g HEC (Natrosol 250 M) into a Glatt GPCG-5 granulator container.
3. Transfer the drug dispersion from Step 2 to a measuring cylinder. Place
the measuring cylinder on the stirrer with a magnet in the measuring cylinder.
25 Connect the measuring cylinder to the Glatt (GPCG-5) granulator through a peristaltic pump.
4. Using an appropriate air volume, inlet temperature, and spray rate,
granulate the material from Step 2 using required amount of drug dispersion to spray
from Step 3.

5. When drug dispersion spray is completed purge with purified water. Dry the granules to a moisture content of not more than 2%.
6. When the moisture content is less than 2%, stop drying and discharge the product. Unload the granules in double transparent polybags.
7. Add colloidal silicon dioxide (e.g. Aerosil) and magnesium stearate to granules of Step 6 and mix.
8. Compress the lubricated granules from Step 7 into tablets using a compression machine equipped with appropriately sized tooling.
For an HEC-based matrix, regardless of the concentration of the polymer in the matrix, it is preferable to compress the granulate using compression equipment that i designed to provide precompression for some stress relaxation (e.g. as traded as Fette 1200 or Elizabeth Hata Model) prior to final compression.
Table 1

Core Components mg/unit
Pseudoephedrine sulphate, USP 240.0
P-cyclodextrin USP, NF (Cavitron™ 82900) 100.0
Dibasic calcium phosphate, dihydrate USP (Emcompress) 150.0
Hydroxyethyl cellulose, USP, NF (Natrosol® 250 M) 360.0
Hydroxypropyl cellulose, NF, EP, JP (Klucel LF) 30.0
Unlubricated granulation, sub-total 880.0
Lubricated granulation total 891.7

Example 2 Heterogeneous Swellable Matrices (HSM) of Pseudoephedrine Sulphate Following the procedure in Example 1 Matrix cores were prepared using the following ingredients recited in Table 2. 5
Table 2

Core Components mg/unit
pseudoephedrine sulphate, USP 240.0
dibasic calcium phosphate, dihydrate USP (Emcompress®) 250.0
hydroxyethyl cellulose, USP, NF (Natrosol 250 M) 360.0
hydroxypropyl cellulose, NF, EP, JP (Klucel LF) 45.0
unlubricated granulation, sub-total 895.0
lubricated granulation total 907.0
Example 3
Heterogeneous Swellable Matrices (HSM) of Pseudoephedrine Sulphate
20 Following the procedure in Example 1 Matrix cores were prepared using the
following ingredients recited in Table 3.
Table 3

Core Components mg/unit
pseudoephedrine sulphate, USP 240.0
P-cyclodextrin USP, NF (Cavitron™ 82900) 120.0
dibasic calcium phosphate, dihydrate USP (Emcompress®) 250.0

hydroxyethyl cellulose, USP, NF (Natrosol®250 M) 240.0
hydroxypropyl cellulose, NF, EP, JP (Klucel® LF) 45.0
unlubricated granulation, sub-total 895.0
lubricated granulation total 907.0
Example 4
10 Heterogeneous Swellable Matrices (HSM) of Pseudoephedrine Sulphate
Following the procedure in Example 1 Matrix cores were prepared using the following ingredients recited in Table 4.
Table 4

Core Components mg/unit
pseudoephedrine sulphate, USP 120.0
dibasic calcium phosphate, dihydrate USP (Emcompress®) 91.0
hydroxyethyl cellulose, USP, NF (Natrosol®250 M) 180.0
hydroxypropyl cellulose, NF, EP, JP (Klucel®LF) 22.6
unlubricated granulation, sub-total 413.6
lubricated granulation total 419.0
25
Example 5 Heterogeneous Swellable Matrices (HSM) of Felodipine Following the procedure in Example 1 Matrix cores were prepared using the following ingredients recited in Table 5.

Table 5

Core Components mg/unit
Felodipine 5.0
P-cyclodextrin USP, NF (Cavitron™ 82900) 318.0
hydroxyethyl cellulose, USP, NF (Natrosol®250M) 68.0
hydroxypropyl cellulose, NF, EP, JP (Klucel® LF) 22.6
unlubricated granulation, sub-total 413.6
lubricated granulation total 4190
Example 6
Heterogeneous Swellable Matrices (HSM) of Pseudoephedrine Sulphate
15 Following the procedure in Example 1 Matrix cores were prepared using the
following ingredients recited in Table 6.
Table 6

Core Components mg/unit
pseudoephedrine sulphate, USP 240.0
dibasic calcium phosphate, dihydrate USP (Emcompress®) 210.0
hydroxyethyl cellulose, USP, NF (Natrosol®250M) 360.0
Hydroxypropyl Cellulose, NF, EP, JP (Klucel® LF) 30.0
unlubricated granulation, sub-total 840.0
lubricated granulation total 851.2

Table 7

Core Components mg/unit
diltiazem malate (eq. To diltiazem HC1180mg) 218.95
dibasic calcium phosphate, dihydrate USP (Emcompress®) 91.0 . _
hydroxyethyl cellulose, USP, NF (Natrosol®250 M) 80.0
Hydroxypropyl Cellulose, NF, EP, JP (Klucel® LF) 23.65
unlubricated granulation, sub-total 413.6
lubricated granulation total 419.0
Examples 8-14 Core Coating Procedure
15 An suitable R&D coating pan such as LDCS 3.75L (Vector Corporation,
New Jersey) is used. The machine configuration includes a standard nozzle type, a 2 mm nozzle port, and standard air pattern. Pan rotation is 20 RPM. For batch sizes ranging from 2-3 kg, the following processing parameters in Table 5 are maintained, after pre-warming is completed. The general coating conditions are recited in Table 20 8.
Table 8

Elapsed
Time
(min.) Inlet Air Temp, °C Product Temp, °C Processing Air Flow, mVhr (CFM) Spray Rate g/min Spray Air, psi
0-30 62 37 (41) 7 19
30-60 64 41 (51) 8 -
Drying 67 44 (52) - -

Example 8 Procedure for Preparing a Composition of Felodipine Cores with a Film Coating Following the procedure set forth above, cores containing felodipine, prepared in Example 5, having an average weight of 419 mg, were coated with a 5 coating having the composition recited in Table 9.
Table 9

mg/core Percent of Core Weight
BASE COAT
Opadry®YS-3-7065 10.475 2.50
ELASTIC COAT
hydroxyethyl cellulose, NF (Natrosol®250L) 8.3800 2.00
talc (Altaic®500V USP) 1.0475 0.25
polyethylene glycol 400 1.0475 0.25
COLORCOAT
Opadry®03-B-53026 Orange 10.475 2.50
TOTAL 31.425 7.50
20
Example 9 Procedure for Preparing a Composition of Felodipine Cores with a Film Coating Following the procedure set forth in Example 8, cores containing felodipine, prepared in Example 5, having an average weight of 419 mg, were coated with a 25 coating having the composition recited in Table 10.

Table 10

mg/core Percent of Core Weight
BASE COAT
Opadry® YS-3-7065 10.475 2.50
ELASTIC COAT „.
hydroxyethyl cellulose, NF (Natrosol® 250 L) 5.866 2.00
talc (Altaic® 500V USP) 0.733 0.25
polyethylene glycol 400 0.733 0.25
hydroxypropyl methyl cellulose including a plasticizer such as PEG 400 3.143
COLOR COAT
Opadry® 03-B-53026 Orange 10.475 2.50
TOTAL 31.425 7.50
Example 10 Composition of Pseudoephedrine Sulfate Cores with a Loratadine Coating 20 A) Base Coating of pseudoephedrine sulfate cores.
1. Disperse Opadry® YS-7065 in purified water while stirring and continue the stirring for 30 minutes. Load the pseudoephedrine cores in a coating pan and warm while "inching" the pan intermittently. The cores are coated with about 22.675 mg each of coating material. 25
B) Hydrophilization of Loratadine in HEC Coating.
1. Disperse 50 g Natrosol 250 L and 50 g Opadry® YS-IR-7006 (contains only polymer of grade E-5, where 5 denotes the viscosity of the polymer) or Opadry Y-5-7065 (contains a blend of one grade E-5 and E-50, where 5 and 50 denote the viscosity

of the polymers) in 1000 ml of purified water by stirring at a medium speed, using a propeller stirrer on a Lightnin® mixer. Allow the dispersion to become foamless. Optionally, an anti-foam agent can be added to remove the foam.
2. Add 50 g micronized loratadine to the Natrosol dispersion prepared in Step
5 1.
3. Microfluidize the drug loaded dispersion of Step 2 using a Microfluidizer
(M-210 EH) at 3,000 to 4,000 PSI and a single discrete pass. This operation will lead
to hydrophilization and deagglomeration of loratadine and render it suitable for film
coating.
10
C) Drug Dispersion Coating
1. Using an appropriate coating equipment designed for film coatings such as Accela-Cota (Thomas Engineering, USA) or Wurster insert in CGPG (Traded y Glatbt Air Techniques, USA), and standard processing parameters suitable for the specific 15 equipment available, apply a theoretical coat of 33 mg on HSM surface.
D) Application of Finish Coat
1. A finish coat of 15% w/w dispersion of hydroxypropyl methyl cellulose (Traded as Opadry Y-S-7095 by Colorcon, USA) in order to deposit a weight gain of 20 2% w/w based on drug loaded cores can be added if desired.
Cores containing pseudoephedrine sulfate, prepared in Example 2, having an average weight of 907 mg, were coated with a coating having the composition recited in Table 11.

Table 11

mg/core Percent of Core Weight
BASE COAT
Opadry®YS-3-7065 22.675 2.50
ELASTIC DRUG COAT
(2% of base-coated cores) ■ —
hydroxyethyl cellulose, NF (Natrosol®250L) 12.698 1.365
talc (Altaic®500V USP) 1.587 0.171
polyethylene glycol 400 1.587 0.171
hydroxypropyl methyl cellulose with a plasticizer e.g., PEG 400 6.8025 0.732
loratadine 10.000 1.075
COLOR COAT
Opadry® Y-22-7719 White (2% of Drug-Coated Cores) 22.675 2.35
TOTAL 78.025 8.36
20 Example 11
Composition of Pseudoephedrine Sulfate Cores with a Descarboethoxy Loratadine
Coating Following the procedure set forth in Example 8, cores containing pseudoephedrine sulfate, 240 mg, having an average weight of 907 mg were coated 25 with the coating composition recited in Table 12.

Table 12

mg/core Percent of Core Weight
BASE COAT
Opadry®YS-3-7065 22.675 2.50
ELASTIC DRUG COAT
(2% of base-coated cores)

Hydroxyethyl Cellulose, NF (Natrosol®250L) 12.698 1.365
Talc (Altaic® 500V USP) 1.587 0.171
Polyethylene Glycol 400 1.587 0.171
Hydroxypropyl methyl Cellulose including a plasticizer such as PEG 400 6.8025 0.732
Descarboethoxy Loratadine 10.000 1.075
COLOR COAT
Opadry®Y-22-7719 White (2% of Drug-Coated Cores) 22.675 2.35
TOTAL 78.025 8.36
20 Example 12
Composition of Felodipine Cores with an Enalapril Maleate Coating. Following the procedure set forth in Example 8, cores containing felodipine, 5.0 mg, prepared in Example 5, having an average weight of 419 mg were coated with the coating composition of enalapril maleate recited in Table 13.

Table 13

mg/Core Percent of Core Weight
BASE COAT
Opadry* YS-3-7065 10.475 2.5
ELASTIC DRUG COAT
(2% of base-coated cores) ~
hydroxyethyl cellulose, NF (Natrosol®250L) 5.866 1.36
polyethylene glycol 400 0.733 0.171
talc (Altaic® 500V USP) 0.733 0.171
hydroxypropyl methyl cellulose including a plasticizer such as PEG 400 3.143 0.732
enalapril maleate 5.000 1.164
magnesium trisilicate 7.333 1.707
P-cyclodextrin 7.333 1.707
COLOR COAT
Opadry®Y-22-7719 White 10.475 2.27
TOTAL 51.091 11.80
20
Example 13 Composition of Diltiazem Cores with an Enalapril Maleate Coating. Following the procedure set forth in Example 8, cores containing diltiazem malate, 218.95 mg, prepared in Example 7, having an average weight of 419 mg 25 were coated with the HEC coating composition recited in Table 14.

Tablc 14

mg/core Percent of C
BASE COAT
Opadry®YS-3-7065 10.475 2.1
ELASTIC DRUG COAT
(2% of base-coated cores)
Hydroxyethyl Cellulose, NF 5.866 1.3
Polyethylene Glycol 400 0.733 0.1
Talc (Altaic®500V USP) 0.733 0.1
Hydroxypropyl methyl Cellulose including a plasticizer such as PEG 400 3.143 0.7
Enalapril Maleate 5.000 1.1
Magnesium Trisilicate 7.333 1.7
P-Cyclodextrin 7.333 1.7
COLOR COAT
Opadry® Y-22-7719 White 10.475 2.:
TOTAL 51.091 11,
20 Example 14
Composition of Pseudoephedrine HC1 Cores with and a Drug Following the procedure set forth in Example 8, cores cc pseudoephedrine sulfate, 120 mg, prepared in Example 4, havin of 419 mg were prepared -with coating, compositions were covvtai 25 drug in the coating. The drugs incorporated in the coating were enalapril, loratadine, descarboethoxy loratadine, or astemizole. the compositions prepared are recited in Table 15.
Table 15

mg/core Percent of Core Weight
BASE COAT
Opadry®YS-3-7065 10.475 2.5
ELASTIC DRUG COAT
(2% of base-coated cores)
hydroxyethyl cellulose, NF (Natrosol®250L) 5.866 1.36
polyethylene glycol 400 0.733 0.171
talc (Altaic® 500V USP) 0.733 0.171
hydroxypropyl methyl cellulose with a plasticizer e.g., PEG 400 3.143 0.732
enalapril, loratadine, descarboethoxy loratadine, or astemizole 5.000 1.193
fumaric acid 7.333 1.707
P-cyclodextrin 7.333 1.707
COLOR COAT
Opadry®Y-22-7719 White 10.475 2.27
TOTAL 51.091 12.193
Example 15 (Drug Release Study') The two drug delivery systems, namely loratadine/pseudoephedrine extended release tablets prepared according to the present invention in Example 9 (LPT-25 012B) and Claritin-D 24 hour (9-DCS-2019) were tested in 900 ml 0.1N HCl maintained at 37°C in U.S.P., Method 2 at 100 RPM. A plot of the percent of pseudoephedrine sulphate released from the test product and the reference product is illustrated in Figure 11. A plot of the percent of loratadine for test product and reference product is illustrated in Figurel2.

Example 16 (Bioavailability Studies)
A single dose of a fixed combination of loratadine and pseudoephcdrine
sulphate dosage forms were administered to 18 fasted subjects in a randomized two-
way crossover manner.
5 Tested Product: loratadine 10 mg + pseudoephedrine sulphate 240 mg
extended release tablet prepared in Example 9.
Reference Product: Claritin® D-24 Hour Tablet of Schering Corp. The particle diameter of the microfluidized dispersion of loratadine for the test product was 25.50 urn (d, 0.9 i.e. 90% below this particle diameter) and 5.85 u.m (d, 10 0.5 i.e. 50% below this particle diameter). Data Analysis
Confidence Intervals and Ratio Analysis: Consistent with two one-sided test for bioequivalence, 90% confidence intervals for the difference between drug formulations (reference and test) least squares means (LSM) are calculated for the 15 parameters AUC0-1 AUCinf and Cmax, using both untransformed and log-transformed data. The confidence intervals are expressed as a percentage relative to the LSM of the reference formulation.
The parameters of bioequivalence are listed in terms of test to reference ratios and 90 percent confidence intervals two one-sided in Tables 16 and 17: 20

Table 16
LORATADINE

Ratio, Test/Reference
(T/R) A two one-sided 90% Confidence interval t-Test for the Ratio of means (T/R) of Bioequivalence Parameters
AUCQ.,, ng/ml. hr AUC0-max ng/ml. hr Cmax ng/ml LnfAUC0-1} Ln{AUC0-inf} LnCCmax 0.88 0.88 0.95 0.86 0.86 0.84 79.04 - 97.54 79.04 - 97.54 77.60 - 112.13 74.77 - 99.08 74.77 - 99.08 70.50 - 100.96
Table 17
PSEUDOEPHEDRINE

Ratio, Test/Reference (T/R) A two one-sided 90% Confidence interval t-Test for the Ratio of means (T/R) of Bioequivalence Parameters
AUC0-1 ng/ml. hr AUC0-infng/ml. hr Cmax ng/ml Ln{AUC0-1} LnfAUC0-max} Ln(C-max) 1.05 1.05 1.23 1.04 1.04 1.22 95.95- 113.91 95.95- 113.91
113.60- 131.49 96.25 112.55 96.25- 112.55
112.96- 132.07
The parameters for bioequivalence is presented below:

AUC0- indicated area under the plasma-time curve and is computed using eithei trapezoidal rule or by defining the curve as a mathematical function (y as a function o] x) and then integrating the function. (Nanogram - hours/ml)
Ln (AUCo-_) is the natural logarithm of the AUC0- value. (Nanogram -5 hours/ml).
C,maxindicates the peak value for drug concentration C in plasma. (Nanogram -hours/ml).
Ln C,max is the natural logarithm of the C,max value. (Nanogram - hours/ml).
All patents, patent applications, and literature cited in the specification are 10 hereby incorporated by reference in their entirety. In the case of any inconsistencies, the present disclosure, including any definitions therein will prevail.
The invention has been described with reference to various specific and preferred embodiments and techniques. However, it should be understood that many variations and modifications may be made while remaining within the spirit 15 and scope of the invention.

WHAT IS CLAIMED IS:
1. A pharmaceutical composition comprising an active agent in a swellable
sustained release delivery matrix said matrix comprising:
a) hydroxyethyl cellulose having a viscosity of from about 4500 to about 6500 cps at 2% by weight in water,
b) an excipient selected from the group consisting of dicalcium phosphate, a cyclodextrin, a hydroxycarboxylic acid, and mixtures thereof; and
c) a binder;
wherein the matrix is surrounded by a water dispersible membrane comprising:
a) a low viscosity hydroxyethyl cellulose;
b) a low viscosity hydroxypropyl methyl cellulose; and
c) a plasticizer.
2. The pharmaceutical composition of claim 1, wherein the active agent is
pseudoephedrine, diltiazem, nifedipme, etodolac, ibuprofen, or felodipine.
3. The pharmaceutical composition of claim 1, wherein the active agent comprises pseudoephedrine.
4. The pharmaceutical composition of claim 1, wherein the active agent comprises felodipine.
5. The pharmaceutical composition of claim 1, wherein the active agent comprises diltiazem.

The pharmaceutical composition of claim 1, wherein the weight ratio of the amount of active agent to the low viscosity hydroxyethyl cellulose is from about 1:2 to about 2:1.
The pharmaceutical composition of claim 1, wherein the weight ratio of active agent to the low viscosity hydroxyethyl cellulose in the matrixes about 0.5 to about 2.0.
The pharmaceutical composition of claim 1, wherein the weight ratio of active agent to the low viscosity hydroxyethyl cellulose in the matrix is about 0.75 to about 1.0.
The pharmaceutical composition of claim 1, wherein the membrane surrounding the matrix comprises a second active agent that is the same or different than the active agent in the matrix.
The pharmaceutical composition of claim 9, wherein the second active agent is present in a ratio to the membrane of from about 1:1 to about 1:10.
The pharmaceutical composition of claim 9, wherein the weight ratio of second active agent to membrane ranges from about 1:3 to about 1:9.
The pharmaceutical composition of claim 11, wherein the weight ratio of second active agent to membrane ranges from about 1:5 to about 1:7.
The pharmaceutical composition of claim 9, wherein the second active agent is microfluidized.

14. The pharmaceutical composition of claims 9 or 13, wherein second active agent is loratadine, descarboethoxy loratadine, tamoxifen, enalapril, astemizole, captopril, or a salts thereof.
15. The pharmaceutical composition of claim 14, wherein the second active agent is loratadine, descarboethoxy loratadine, enalapril, or astemizole.
16. The pharmaceutical composition of claim 14, wherein the second active agent is loratadine, descarboethoxy loratadine or astemizole.
17. The pharmaceutical composition of claim 14, wherein the second active agent is microfluidized loratadine, microfluidized descarboethoxy loratadine, or microfluidized astemizole.

18. The pharmaceutical composition of claim 14, wherein the second active agent is loratadine, or descarboethoxy loratadine.
19. The pharmaceutical composition of claim 14, wherein second active agent is loratadine.
20. The pharmaceutical composition of claim 14, wherein the second active agent is descarboethoxy loratadine.
21. The pharmaceutical composition of claim 14, wherein the second active agent is astemizole.
22. The phannaceutical composition of claim 14, wherein the second active
agent is enalapril buffered with magnesium trisilicate.

23. The pharmaceutical composition of claim 1, wherein the hydroxyethyl cellulose in the matrix has a molecular weight of about 500,000 to about 800,000.
24. The pharmaceutical composition of claim 1, wherein the weight ratio of the hydroxyethyl cellulose to the excipient is from about 1:3 to about 3:1 by weight.
25. The pharmaceutical composition of claim 25, wherein the weight ratio of the hydroxyethyl cellulose to the excipient is about 1:1.5 to about 1.5:1.
26. The pharmaceutical composition of claim 1 ;wherein the excipient comprises dicalcium phosphate dihydrate.
27. The pharmaceutical composition of claim 1, wherein the excipient comprises a cyclodextrin.
28. The pharmaceutical composition of claim 1, wherein the cyclodextrin is α-cyclodextrin,β-cyclodextrin, γ-cyclodextrin, dimethyl - β-cyclodextrin or hydroxyethyl - β-cyclodextrin.

29. The pharmaceutical composition of claim 1, wherein the cyclodextrin is P-cyclodextrin.
30. The pharmaceutical composition of claim 1, wherein the binder is sodium alginate, sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl cellulose ("HPC"), or polyvinyl pyrrolidone.
31. The pharmaceutical composition of claim 1, wherein the binder is hydroxypropyl cellulose.

32. The pharmaceutical composition of claim 30, wherein the hydroxypropyl cellulose in the matrix has a particle size range such that 85% by weight passes through a 30 mesh screen and 99% by weight passes through a 20 mesh screen.
33. The pharmaceutical composition of claim 1, wherein the weight ratio of the hydroxyethyl cellulose to the hydroxypropyl methyl cellulose in the matrix is from about 10:1 to about 1:1.
34. The pharmaceutical composition of claim 1, wherein the weight ratio of the hydroxyethyl cellulose to the hydroxypropyl methyl cellulose in the matrix is from about 9:1 to about 1:2.
35. The pharmaceutical composition of claim 1, wherein the weight ratio of the hydroxyethyl cellulose to the hydroxypropyl methyl cellulose in the matrix is from 3:2 to 1:4.

36. The pharmaceutical composition of claim 1, wherein the matrix comprises a hydroxycarboxylic acid is selected from the group consisting of citric acid, tartaric acid, ascorbic acid, gluconic acid, citric acid, malic acid, lactic acid, and treonic acid.
37. The pharmaceutical composition of claim 35, wherein the hydroxycarboxylic acid is selected from the group consisting of citric acid, tartaric acid, and malic acid.
38. The pharmaceutical composition of claim 37, wherein the acid is in combination with a cyclodextrin.

39. The pharmaceutical composition of claim 1, wherein the membrane comprises hydroxyethyl cellulose having a number average molecular weight distribution of between 75,000 and 100,000.
40. The pharmaceutical composition of claim 38, wherein the hydroxyethyl cellulose in the membrane is about 80-90% hydroxyethoxy substituted.
41. The pharmaceutical composition of claim 1, wherein the membrane comprises hydroxyethyl cellulose having an aqueous solution viscosity of from about 14 to about 1280 cps at 2% by weight in water.
42. The pharmaceutical composition of claim 39, wherein the membrane comprises hydroxyethyl cellulose having a viscosity of about 75 to about 150 cps at 5% by weight in water.
43. The pharmaceutical composition of claim 39, wherein the membrane comprises hydroxyethyl cellulose having a viscosity of about 80 to about 125 cps at 5% by weight in water.

44. The pharmaceutical composition of claim 1, wherein the membrane comprises hydroxypropyl methyl cellulose that is a blend of polymers having viscosities of about 5 to about 50 cps at 2% by weight in water.
45. The pharmaceutical composition of claim 44, wherein the membrane comprises hydroxypropyl methyl cellulose having a number average molecular weight distribution of about 8,000 to 14,000 and a viscosity from about 3 to about 15 cps in a 2% by weight water solution at room temperature.
42

46. The pharmaceutical composition of claim 1, wherein the plasticizer is triethyl citrate, triacetin, propylene glycol, glycerol monostearate, or polyethylene glycol.
47. The pharmaceutical composition of claim 46, wherein the plasticizer is polyethylene glycol 400.
48. The pharmaceutical composition of 1, wherein the membrane comprises hydroxyethyl cellulose with 83.3 % substitution of hydroxy groups in the cellulose by hydroxyethoxy groups; and
a polymer selected from the group consisting of hydroxypropyl methyl cellulose with 28-30% methoxy-substitution of hydroxy groups in the cellulose or an hydroxyalkyl cellulose with 30-50% substitution of hydroxy groups in the cellulose with hydroxyethoxy groups.
49. The pharmaceutical composition of 1, wherein the swellable sustained release
delivery matrix comprises:
hydroxyethyl cellulose having a viscosity of about 4500 to about 6500 cps at 2% by weight in water, P-cyclodextrin; dicalcium phosphate dihydrate; hydroxypropyl cellulose; and an active agent;
wherein the weight ratio of the hydroxyethyl cellulose to the dicalcium phosphate dihydrate is about 1:3 to about 3:1 by weight.
50. The pharmaceutical composition of claim 48,wherein the composition is
surrounded by a membrane coating the matrix and wherein the coating
comprises a second active agent that is the same or different than the active
agent in the matrix, a plasticizer, a low viscosity hydroxyethyl cellulose, and
a low viscosity hydroxypropyl methyl cellulose, and wherein the membrane
is elastic and resistant to cracking.

51. The pharmaceutical composition of claim 1, wherein the matrix comprises an
active agent; hydroxyethyl cellulose having viscosity of 4500 to about 6500
cps at 2% by weight in water; beta-cyclodextrin, hydroxypropyl cellulose and
dicalcium phosphate dihydrate;
wherein the weight ratio of the hydroxyethyl cellulose to the dicalcium phosphate dihydrate is from about 1:3 to about 3:1 by weight; and
a membrane surrounding the matrix comprising a second active agent that is the same or different than the first active agent, a plasticizer, hydroxyethyl cellulose having a viscosity of about 75 to about 150 cps at 5% by weight in water, and hydroxypropyl methyl cellulose; and wherein the membrane is elastic and resistant to cracking.
52. The pharmaceutical composition of claim 51, wherein the active agent in the
matrix is pseudoephedrine and the second active agent is loratadine.
5 3. The pharmaceutical composition of claim 51, wherein the active agent in the matrix is pseudoephedrine and the second active agent is loratadine.
54. The pharmaceutical composition of claim 51, wherein the active agent in the matrix is pseudoephedrine and the second active agent is descarboethoxy loratadine.
55. The pharmaceutical composition of claim 51, wherein the active agent in the matrix is pseudoephedrine and the second active agent is enalapril.
56. The pharmaceutical composition of claim 51, wherein the active agent in the matrix is felodipine and the second active agent is enalapril.
57. The pharmaceutical composition of claim 51, wherein the active agent in the matrix is diltiazem and the second active agent is enalapril.

58. A method of making the matrix of claim 1, comprising:
combining the binder with water in an amount of about 1-10% by weight to form a first composition;
combining the active agent, the hydroxyethyl cellulose, and the dicalcium phosphate dihydrate in a granulator to form a second composition;
forming granules from the first and second compositions;
drying the granules to a moisture content of less than 3% by weight;
lubricating the granules ; and
compressing the granules.
59. A process for the manufacture of a matrix within a flexible membrane
comprising
i) coating a solid shaped matrix with a water content of less than 3% by weight, with an aqueous coating composition comprising
a) a low viscosity hydroxyethyl cellulose;
b) a low viscosity hydroxypropyl methyl cellulose; and
c) a plasticizer, and
ii) drying the coating composition.
60. The process of claim 59, wherein the coating composition comprises a second active agent.
61. The process of claim 59, wherein the second active agent is loratadine, descarboethoxy loratadine, enalapril, astemizole or a salt thereof.
62. The process of claim 59, wherein the second active agent is loratadine or descarboethoxy loratadine.

63. The process of claim 59, wherein the coating composition is formed at least in part by microfluidization of the active agent, a), b) and c) at a pressure of from about 1,000 to about 20,000 pounds per square inch.
64. The process of claim 59, wherein the coating composition is formed at least in part by microfluidization of the active agent, a), b) and c) at a pressure of from about 3,000 to about 8,000 pounds per square inch.