FORM 2
THE PATENTS ACT 1970
(39 of 1970)
AND
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION:
"NOVEL SUSTAINED-RELEASE GASTRORETENTIVE DOSAGE FORM OF
ACICLOVIR"
2.APPLICANT(S): (a) NAME: FDC LIMITED
(b) NATIONALITY: Indian company incorporated under the Companies
Act, 1956
(c) ADDRESS: 142-48, S.V.Road, Jogeshwari (West), Mumbai - 400 102,
Maharashtra, India.
3. PREAMBLE TO THE DESCRIPTION:
The following specification particularly describes the invention and the manner in which it is to be performed.

Field of Invention
The present invention relates to a novel sustained-release (SR) gastroretentive dosage form of Aciclovir comprising a gastroretentive, pH-independent swellable and mucoadhesive matrix system. The Aciclovir SR tablet of the present invention exhibits improved bioavailability and patient compliance, and reduced adverse drug reactions (ADRs) and dosing frequency.
Background of the invention
Acyclovir is an antiviral drug widely used in the treatment of Herpes simplex virus and Varicella zoster virus infections. It is a synthetic purine nucleoside analogue, which is phosphorylated intracellularly by viral kinase and host cell enzymes, to become inhibitor of viral DNA synthesis. Oral administration of Acyclovir is the most practical and accepted route for the treatment of viral infections.
Conventional immediate-release (IR) tablets of Acyclovir need to be administered 5 times a day which significantly affects patient compliance. Moreover, long term administration (>6 months) of acyclovir is necessary in immunocompetent patient with relapsing Herpes simplex infection. Thus, higher frequency of drug administration provides poor medication compliance and subsequent poor treatment outcome. The immediate release of acyclovir further causes high fluctuation in drug plasma concentration, which leads to side effects and adverse drug reactions. Therefore, an acyclovir dosage form that could be administered with lesser frequency and has reduced adverse drug reactions is desired.
Acyclovir has low solubility and low permeability and hence classified as a BCS class IV drug. Furthermore, the drug has a high dose, a short plasma half life of 2.5 - 3.3 hours and low bioavailability. Due to these limitations, conventional Aciclovir immediate release dosage form needs to be taken 5 times a day. Moreover, Acyclovir shows capacity-limited intestinal absorption and hence the drug uptake after oral administration does not increase proportionately with increase in the dose. As a result, with increase in drug dosing, there is decrease in drug bioavailability.
Therefore, the presently available conventional dosage forms of acyclovir are associated with various drawbacks such as high dosing frequency of 5 times a day, along with low

bioavailability (10-20%), highly variable drug absorption and adverse drug reactions after oral administration, which leads to poor treatment outcome.
The aforementioned problems can be solved by developing controlled-release drug delivery systems, which deliver a therapeutic drug in a controlled manner within a particular therapeutic window, so that effective and safe blood levels are maintained for a period as long as the system continues to deliver the drug at a particular rate. Such controlled delivery usually results in substantially constant blood levels of the therapeutic drug as compared to fluctuations observed with immediate release dosage forms. Gastroretentive dosage forms serve as controlled-release drug delivery systems, and remain in the gastric region for a long period of time, thus significantly prolonging the drug release and improving drug bioavailability. Ample literature is available on gastroretentive dosage forms as listed below.
WO2010035273 discloses a gastroretentive delivery system based on the use of three different gastroretentive mechanisms, floatation, swelling and mechanical strength, which are acting in a complimentary way. The gastroretentive tablet comprises active ingredient, gas generating agent, unrestricted swelling ingredient and swelling restricting ingredient.
Current Drug Delivery (2009), 6(5), 437-443 article titled "Preparation and evaluation of gastroretentive floating tablets of acyclovir" discloses preparation and evaluation of floating tablets of acyclovir as model drug for prolongation of gastric residence time, wherein the floating effervescent tablets are formulated by various materials like hydroxypropyl methylcellulose K 4M, K 15M, psyllium husk, swelling agent as crospovidone and microcrystalline cellulose and gas generating agent like sodium bicarbonate and citric acid. These floating effervescent tablets were prepared by polypropylene foam powder and different matrix forming polymers like HPMC K 4M, Carbopol 934P, xanthan gum and sodium alginate.
WO2009150514 discloses a process for making oral solid gastroretentive forms, comprising the steps of (i) providing a powder mixture of a hydrophobic powder, (ii) overgranulating this powder mixture with a granulating solution into an overgranulated paste, and (iii) drying said paste into a solid, as well as pharmaceutical solid dosage forms

which are retained in the stomach or upper gastrointestinal tract for a controlled delivery of a drug.
WO2009153632 discloses gastroretentive pharmaceutical dosage form which contains active ingredient and polymeric adjuvant. The adjuvant serves to retain the dosage form in a selected region of the gastrointestinal tract for sufficient time for the pharmaceutically active ingredient to be released and absorbed. The dosage form contains two or more pharmaceutically active ingredients which are delivered to different regions of the gastrointestinal tract.
US5972389 discloses controlled release dosage form containing several particles of a solid state drug dispersed in a swellable/erodible polymer, such as polyethylene oxide. The oral dosage form, once ingested, disintegrates to disperse the particles within the stomach where the particles imbibe water to swell and promote retention in fed-mode-induced patients. As the gastric retained dosage form gradually erodes, the drug is released in a controlled manner to the stomach for treatment of local disorders, and to the upper gastrointestinal tract where it becomes available for absorption in a controlled and therapeutic manner. Drug containing vesicles such as liposomes or nanoparticles, or enteric coated drug particles, can also be delivered to the gastrointestinal tract in a controlled manner using the gastric retentive dosage forms. The patent discloses preparation of controlled release dosage form of Acyclovir, wherein Acyclovir, polyethylene oxide and magnesium stearate are dry-mixed, pre-compressed and dry-milled, and an additional amount of magnesium stearate was combined with the milled granulation and directly compressed to give tablets, which are then filled into a capsule (3 tablets per capsule).
EP1972332 discloses a mucosal bioadhesive slow release carrier comprising an active principle, which can release the active principal for a duration of longer than 20 hours. The bioadhesive carrier contains at least one bioadhesive natural protein of vegetal origin and at least one sustained release polymer. The patent also discloses a method for preparation of mucosal bioadhesive slow release carrier, wherein acyclovir, microcrystalline cellulose and sodium lauryl sulfate are premixed; and polyvinylpyrrolidone dissolved in purified water, is added to the mix, stirred and then

granulated to form the primary granules. Further, mucoadhesive agent (pea protein or milk cone, protein, carbopol 974 or chitosan), hypromellose, magnesium stearate and colloidal silica are added to the primary granules to form the final blending mixture, which is then compressed into tablets.
CN101647786 discloses Acyclovir sustained-release tablets and its preparation method thereof. The acyclovir sustained-release tablet is composed of acyclovir, slow-release material, pore-causing agent, diluting agent, adhesives and lubricants. The slow-release material is selected from hydroxy propylcellulose, ethylcellulose, methylcellulose, cellulose phthalate acetate, hydroxy propyl cellulose, carboxy methy! cellulose, sodium carboxy methyl cellulose, hydroxy ethyl cellulose, cellulose acetate, cellulose diacetate, cellulose triacetate, hydroxy methyl cellulose. The pore-causing agent comprises one or more of microcrystalline cellulose, lowly substituted hydroxy propyl cellulose, polyvinyl alcohol, polyethylene glycol, sodium alginate, chitosan, sucrose and lactose. The diluting agent comprises microcrystalline cellulose, mannitol, lowly substituted hydroxy propylcellulose, polyvinyl alcohol., vinyl acetate phthalate, polyethylene glycol and/or ethanol. The adhesives comprise water, ethanol, absolute ethanol, starch slurry, povidone, crosslinked polyvinyl pyrrolidone, hydroxy propyl methyl cellulose and/or other celluloses.
IN 205078 discloses a process for the manufacturing of floating, swellable and bioadhesive sustained release dosage forms comprising a powder of drug(s) in a floating, swellable and bioadhesive carrier composition, wherein the drugs are compatible with each other and are mainly used for sustained release formulation preferably, once a daily formulation. The novel bioadhesive carrier composition comprises a gel-forming and bioadhesive fiber, swelling agents, hydrophilic water soluble polymer(s), a gas generating agent and excipients, along with a channeling agent to increase initial burst release of the drug.
None of the aforementioned prior arts have attempted to develop Acyclovir solid oral dosage forms having reduced dosing frequency with better treatment outcome and reduced adverse drug reactions. Therefore, the present inventors have developed a novel sustained-release (SR) gastroretentive dosage form of Aciclovir with thrice a day

administration, using a gastroretentive, pH-independant swellable, mucoadhesive matrix system to overcome the problems of high dosing frequency, poor patient compliance, low bioavailability and poor treatment-outcome.
Object of Invention
The main object of the invention is to develop a sustained-release gastroretentive solid dosage form of Aciclovir which offers reduced dosing frequency with better treatment outcome and hence improves patient compliance.
Another object of the invention is to develop a sustained-release gastroretentive solid dosage form of Aciclovir which exhibits improved bioavailability with least fluctuation in plasma drug concentration, and lesser tendency to cause side effects leading to reduced adverse drug reactions.
Summary of the invention:
In accordance with the above objectives, the present invention provides a novel sustained-release (SR) gastroretentive dosage form of Aciclovir comprising a gastroretentive, pH-independent swellable and mucoadhesive matrix system.
The matrix system of the present invention comprises pH-independent hydrophilic-swellable, mucoadhesive polymers, a channeling agent and pharmaceutically acceptable excipients. The said pH-independent hydrophilic-swellable, mucoadhesive polymers consist of a combination of a low-viscosity polymer and a high-viscosity polymer.
The Aciclovir SR tablet of the present invention has reduced dosing frequency of three times a day, improved bioavailability and patient compliance, and reduced adverse drug reactions (ADRs), which in turn provides better treatment outcome in patients suffering from Herpes simplex virus and Varicella zoster virus infections.

Description of drawing:
Fig 1 depicts the comparative study of drug plasma concentration of test and reference products
Detailed Description of invention
The invention will now be described in detail in connection with certain preferred and optional embodiments, so that various aspects thereof may be more fully understood and appreciated.
Acyclovir exhibits two pKa values of 2.27 and 9.25. Therefore, even though. Acyclovir is a poorly soluble drug, it has relatively better solubility in acidic pH of the stomach along with duodenal absorption, and hence Acyclovir proves to be an ideal candidate for gastroretentive dosage form.
The present invention provides a novel sustained-release (SR) gastroretentive dosage form of Aciclovir with thrice a day administration, comprising a gastroretentive, pH-independent swellable, mucoadhesive matrix system.
The matrix system of the present invention comprises pH-independent hydrophilic-swellable, mucoadhesive polymers, a channeJing agent and pharmaceutically acceptable excipients. The said pH-independent hydrophilic-swellable, mucoadhesive polymers consist of a combination of a low-viscosity polymer and a high-viscosity polymer.
The matrix system consisting of the innovative combination of high and low viscosity polymers, offers better consistency in drug release and thus provides slow and sustained release of acyclovir from the dosage form. These hydrophilic swellable polymers in the matrix system, swell independent of the pH of the matrix after hydration, and thus enable pH-independant swelling of the matrix system. Moreover, the hydrophilic swellable polymers present in the matrix system are mucoadhesive and hence stick to the gastric mucosa, which supports prolonged retention of acyclovir in the stomach and provides sustained release of acyclovir for a longer period of time.

Due to the pH-independent hydrophilic-swellable, mucoadhesive polymers present in the matrix system, the tablet swells after hydration to a size greater than that of the dilated pyloric end, and this swelled tablet retains in the stomach for at least 4-6 hrs which in turn provides a slow and sustained release pattern of acyclovir for a long period of time. Moreover, the hydrophilic swellable polymers present in the matrix system are mucoadhesive, thus enabling the matrix system and subsequently the tablet to stick to the gastric mucosa, which supports prolonged retention of acyclovir in the stomach and provides sustained release of acyclovir for a longer period of time. The mucoadhesive polymers have strong affinity with gastric mucosa and hence provide prolonged gastroretention, which favors the drug absorption.
The matrix system being pH-independent swellable system, ensures pH-independent swellability of the tablet on administration, independent of a fed /fasted state of the patient, which means the tablet swells independent of the stomach acidity of the patient to offer consistent and controlled release of acyclovir from the dosage form and desired pharmacokinetic profile. Further, the matrix system being gastroretentive and mucoadhesive, ensures that the tablet is retained in the stomach for a longer period of time to provide sustained release of acyclovir from the dosage form,
Thus, the matrix system of the present invention ensures that acyclovir is retained in the stomach and released in a consistent and controlled manner from the dosage form to provide slow and sustained release pattern, which results in better absorption of acyclovir in small intestine, while minimizing fluctuation in the plasma drug concentration. As a result, the Aciclovir SR tablet of the present invention provides improved bioavailability, reduced dosing frequency of three times a day and reduced adverse drug reactions (ADRs).
The Aciclovir SR tablet of the present invention is to be administered three times a day as compared to 5 times a day administration of conventional immediate-release (IR) acyclovir tablets, thus improving patient compliance. Additionally, the maximum daily dose of Aciclovir is not exceeded in the sustained-release dosage form of the present

invention. The Acyclovir SR tablet of the present invention comprises 1200 mg of Acylovir.
The hydrophilic swellable polymers present in the matrix system of the present invention are a combination of low-viscosity polymer and high viscosity polymer.
The low-viscosity polymer used in the present invention is selected from hydroxypropylmethylcellulose (viscosity: 80-120 cPs), hydroxypropy!cellulose(viscosity: 75-150 cPs or sodium caboxymethylcellulose (viscosity: 50-200 cPs), present in an amount of 1% to 30% w/w of the total composition.
The high-viscosity polymer used in the present invention is selected from hydroxypropylmethylcellulose (viscosity: 3000-5600 cPs), hydroxypropylcellulose (viscosity: 1500-3000) or hydroxyethylcellulose (viscosity : 3400 - 5000 cPs) present in an amount of 5% to 40% w/w of the total composition.
The channeling agent used. in the present invention is selected from hydroxypropylmethylcellulose (viscosity: 5 cPs), polyethylene glycol 4000, polyethylene glycol 10000, sorbitol, mannitol or polyvinyl pyrrolidone present in an amount of 2% to 10% w/w of the total composition
The pharmaceutically acceptable excipients used in the present invention are selected from diluents, glidants, lubricants and anti-adherants selected from the group consisting of microcrystalline cellulose, magnesium stearate, sodium stearate, stearic acid, talc, colloidal silicondioxide, polyethylene glycol, mannitol, carbopol etc. The Aciclovir SR tablet of the present invention is prepared by conventional manufacturing methods such as direct compression, dry and wet granulation.
The Aciclovir SR tablet of the present invention is a pH-independent swellable and mucoadhesive dosage form useful in treatment of Herpes simplex virus and Varicella zoster virus infections. It provides reduced dosing frequency of three times a day, improved bioavailability, and improved patient compliance and reduced adverse drug

reactions (ADRs), which in turn provides better treatment outcome in patients suffering from Herpes Zoster, Herpes simplex and varicella zoster infections.
Bioequivalence Studies:
A randomized, open labeled, balanced, two-treatment, two-period, two-sequence, single-dose, cross-over, bioequivalence study was carried out using Aciclovir I200mg sustained release tablets (3 times/day) of the present invention as a test product, and conventional Aciclovir 800 mg IR tablets (5 times/day) as a reference product. The fasting state study was done using 12 (+2) healthy, adult, male, human subjects. The bioavailability studies revealed the pharmacokinetics of the test and reference products as shown in Table I.
Table 1: Comparative Evaluation of Extrapolated Log transformed Pharmacokinetic Parameters of the Test and Reference products

The comparative evaluation of log-transformed dose normalized pharmacokinetic data in Table 1, indicated that the test product was bioequivalent to the reference product. Hence, the 1200 mg thrice a day tablet of the present invention is bioequivalent equivalent to 800 mg conventional dosage form administered 5 times a day.
A bioavailability study was carried out using Aciclovir I200mg sustained release tablets (3 times/day) of the present invention as a test product, and conventional Aciclovir 800 mg IR tablets (5 times/day) as a reference product. The comparative study of drug plasma concentration of test and reference products is shown in fig I. The comparative study of

evaluation of drug plasma concentrations indicated that the test product was bioequivalent to the reference product.
Clinical Studies:
Multicentric, prospective, randomized, open-label, active-controlled, parallel group clinical studies were carried out in which, Aciclovir 1200mg sustained release tablets (test product) of present invention having 3 times daily administration was compared with conventional Aciclovir 800 mg immediate release (IR) tablets (reference product) having 5 times daily administration for treatment of uncomplicated Herpes zoster in immunocompetent adult patients, for 100% healing of lesions as a primary end point parameter and 100% loss of pain as a secondary end point parameter. The patients had to follow up site visit, maximum 6 times during the study period i.e. visit 1 (Day 0), visit 2 (Day 4), visit 3 (Day 8) and visit 4 (Day 15), visit 5 (Day 22) and visit 6 (Day 29).
Primary End Point Evaluation:
Table 2: Comparative evaluation of cumulative cure of 100% healing of lesions of test
and reference products

Secondary End Point Evaluation:
Table 3: Comparative Evaluation of Proportion of 100% loss of pain of test and reference products.


'Chi-Square Test p Value
Statistical analysis of the clinical study results revealed that there was no significant difference in the rate of healing of 100% lesions between the test and reference product (p>0.05 level of significance, Fisher's Exact Test) (Table 2)
Patient proportion of 100% loss of pain was 71.74 % for test product and 63.64% for reference product respectively. The test product is more effective than the reference product in showing 100% loss of pain on study completion (Table 3) (p> 5% level of significance, Chi-Square Test).
Seventeen adverse effects were reported in the clinical study out of which seven events were occurred in test product treated subjects (12.50%) and ten ADR were reported in reference drug treated subjects (17.86 %). The adverse effects were mild to moderate in severity and resolved. No death, other serious adverse event and other significant adverse event was reported during the study period.
In conclusion, test product Aciclovir 12Q0mg sustained release tablets was found more effective and safe as reference product Acyclovir 800mg immediate release tablets for treating uncomplicated Herpes zoster in immunocompetent adults. The reduced dosing frequency of test product improves patient compliance and hence contributes to improved treatment outcome.

Examples: Example 1
Aciclovir 1200mg sustained release tablet:

Sr.
No Ingredients mg/tab
1. Aciclovir 1200
2. Macrocrystalline Cellulose 80
3. Hydroxypropylmethylcellulose (viscosity: 80-100 cPs) 120
4. Hydroxypropylmethylcellulose (viscosity: 3600-5000 cPs) 70
5. Hydroxypropylmethylcellulose (5 cPs) 30
6. Talc 15
7. Colloidal Silicon Dioxide 7
8. Magnesium Stearate 13
Example 2

Sr.
No Ingredients mg/tab
1. Aciclovir 1200
2. Microcry stall ine Cellulose 80
3. Hydroxypropyl cellulose (3400-5000 cPs) 140
4. Hydroxypropyl cellulose (75-150 cPs) 50
5. Polyethylene glycol 4000 25
6. Talc 15
7. Colloidal Silicon Dioxide 7
8. Stearic Acid 10

Example 3

Sr.
No Ingredients mg/tab
I. Aciclovir 1200
2. Microcrystalline Cellulose 80
3. Hydroxypropylmethylcellulose (3400-5000 cPs) 100
4. Sodium CMC (50-200 cPs) 50
5. Mannitol 25
6. Talc 15
7. Colloidal Silicon Dioxide 7
8. Sodium Stearyl Fumarate 8
Example 4

Sr.
No Ingredients mg/tab
1. Aciclovir 1200
2. Microcrystalline Cellulose 80
3. Hydroxypropylmethylcellulose (80-120 cPs) 90
4. Carbopol 940 80
5. Mannitol 25
6. Talc 15
7. Colloidal Silicon Dioxide 7
8. Magnesium Stearate 13

We claim:
1. A sustained-re lease gastroretentive dosage form of Aciclovir comprising a gastroretentive, pH-independent swellable and mucoadhesive matrix system.
2. The sustained-release gastroretentive dosage form of Aciclovir as claimed in claim 1, wherein the matrix system comprises pH-independent hydrophilic-swellable, mucoadhesive polymers, a channeling agent and pharmaceutically acceptable excipients.
3. The sustained-release gastroretentive dosage form of Aciclovir as claimed in claim 2 wherein the pH-independent hydrophilic-swellable, mucoadhesive polymers consist of a combination of a low-viscosity polymer and a high-viscosity polymer.
4. The matrix system as claimed in claim 3, wherein the low-viscosity polymer is selected from hydroxypropylmethylcellulose (viscosity: 80-120 cPs), hydroxypropylcellulose (viscosity: 75 - 150 cPs) or sodium caboxymethylcellulose (viscosity: 50-200 cPs).
5. The matrix system as claimed in cJaim 3, wherein the high-viscosity polymer is selected from hydroxypropylmethylcellulose (viscosity: 3000-5600 cPs), hydroxypropylcellulose (viscosity: 1500-3000 cPs) or hydroxyethylcellulose (viscosity : 3400 - 5000 cPs).

6. The matrix system as claimed in claim 2, wherein the channeling agent is selected from hydroxypropyl methyl cellulose (viscosity: 5 cPs), polyethylene glycol 4000, polyethylene glycol 10000, sorbitol, mannitol or polyvinyl pyrrolidone.
7. The matrix system as claimed in claim 2, wherein the pharmaceutically acceptable excipients are selected from diluents, glidants, lubricants and anti-adherants.
8. The sustained-release gastroretentive dosage form of Aciclovir as claimed in claim 1 is an Aciclovir SR tablet havings dosing frequency of thrice a day.
9. The sustained-release gastroretentive dosage form of Aciclovir as claimed in claim 1, wherein the matrix system being pH-independent swellable, ensures pH-independent swellability of the tablet on administration, independent of a fed /fasted state of a patient.