Title of Invention

"A PROCESS FOR THE PREPARATION OF PHARMACEUTICAL COMPOSITION OF CIPROFLOXAZEN"

Abstract The present invention discloses a process for the preparation of pharmaceutical composition in the form of controlled release once a day formulation comprising an active ingredient such as ciprofloxacin (78-84% w/w); an in-situ gas forming agent (5-10% w/w); a swellable polymer selected from hydroxypropyl methyl cellulose (5-12% w/w) or poly (ethylene oxide) (1-6% w/w) and optionally having a fast dissolving film forming coating and an auxiliary pharmaceutically acceptable excepient comprising the steps of (a) binding ciprofloxacin with a solution of copolyvidone or hydroxy propylmethyl cellulose and kneading the same to form a wet mass (b) drying and sizing the wet mass to form ciprfloxacin drug granules (c ) binding sodium bi-carbonate with solution of providone in isopropyl alcohol and drying the same in a fluidized bed dryer to get sodium bi-carbonate granules (d) mixing the ciprofloxacin with poly(ethylene oxide) or hydroxy propylmethyl cellulose and sodium bi-carbonate granules thus obtained with lubricants (e) compressing into tablets and coating the same.
Full Text The present invention relates to a process for the preparation of pharmaceutical composition in the form of controlled release once a day formulation particularly with the drug ciprofloxacin . The pharmaceutical form of the present invention is designed for controlled release of the active ingredients that exhibit a small absorption window in the first portion of the gastrointestinal tract, i.e. in the stomach or the upper part of the small intestine.
The instant patent application has been divided out of Indian patent application No. 723/CAL/2001
A controlled release dosage form is one that delivers the physiologically active substance in a planned, predictable and slower than normal manner for longer period of time at a predetermined rate and thus reduces the drug plasma fluctuations commonly observed when multiple doses of immediate release conventional dosage forms are administered to a patient. The most common types of controlled release products are oral dosage forms. These products normally proceed for a 12 or 24 hour dosing interval. Dosing intervals for oral controlled release products beyond once a day dosing are limited by physiological characteristics of human gastrointestinal tract.
There are various methods of developing molecules for traditional oral drug delivery system. Kariji Takada (Encyclopedia of control drug delivery vol.2,

pp. 729), describes a detail list of various mechanisms, which are used for the gastro-retentive drug delivery system.
A variety of oral controlled release drug delivery systems based on different release mechanism have been reported, for example, dissolution controlled systems, diffusion controlled systems, osmotically engineered systems, ion exchange resin erodible matrix system, etc.
Per-oral administration is the route of choice for controlled release formulations due to obvious reasons. Controlled release administration forms described above are utilizable for drug absorbed effectively all through the gastrointestinal tract. These systems are not suitable for many drugs either due to their physicochemical properties or adaptation of carrier mediated transport, active transport or other specific transport mechanisms for effective absorption. These drugs are known to have so called "absorption window". The term "absorption window" states the fact that a drug will be absorbed from a limited region of gastrointestinal tract upon per oral administration of a drug or drug preparation. Most, if not all drugs usually pass from stomach to small intestine in an actually short time period, generally one to two hours. This fact often creates a need of frequent dosing of the agent in order to maintain desired plasma concentration. Such drugs, if formulated according to conventional controlled release systems mentioned in prior art, will not achieve their optimum therapeutic level to guarantee a long-term action. Furthermore, an important factor that restricts one to adopt prior art is that for majority of drugs, absorption from colon is usually erratic and incomplete. Thus controlled release system briefly mentioned above cannot be explored successfully for some specific categories like antibiotics e.g. cefuroxime axitel, which is well absorbed till the distal part of small intestine, but drug released in colon will be consumed by

local bacteria and accidentally may lead to ailments like ulcerative colitis and drug resistance.
It has been found difficult to alter transfer time of active agent through small intestine, although some emphasis has been given on attempting to control transit time of administration form in stomach. Drais et.al (Int. J. Pharm. 21,331-340, 1984) reported that gastrointestinal transit time of a pharmaceutical dosage form depends upon several factors as shape, size and nature of formulation and physiological condition of the stomach. Physiological behavior of the stomach is usually determined by whether it contains food or is empty. As the stomach undergoes contractions it breaks down the digestive materials to 2 mm or less before they pass through the pylorus into duodenum and non-digestive material is retropropelled into main part of stomach for further digestions. Non-digestive material is not generally able to leave the stomach in the fed state. At the end of digestive period retention of non-digestive material is further complicated by the ability of gastrointestinal tract to undergo powerful contractions called inter-digestive myoelectric motor complex or IMMC. IMMC's "housekeeper wave" (PHASE HI activity) tends to sweep non-digestive materials from stomach into duodenum. Consequently a need exists for a controlled release device that not only can deliver the drug for extended period of time but also can retain itself in stomach for a significantly longer period, whether in fed or fasted state.
Shell et al (WO 097/47285), claims an extended release delivery systems for gastric retention that includes a water swellable particulate matrix impregnated with the drug combined with a chemical agent such as serotonin receptor antagonists, fatty acids and/or salts thereof and tryptophan that pharmacologically induces the fed mode in patient's stomach. It is self evident that these fed mode inducing substances specially 5 HT antagonists are all therapeutically active substances and will give their undesirable pharmacological

response like nausea, vomiting, insomnia etc. on long-term therapy with dosage forms containing them.
Talwar et al (US 6,261,601) discloses an orally effective controlled gas powered system providing temporal and spatial control. This multicomponent system comprises a drug, a swelling agent, a viscolyzing agent, a gas generating component and optionally a gelling polymer. The extent of drug loading is 69.9%w/w of ciprofloxacin base . The tablets were prepared by the steps of mixing, roll compaction, sieving, blending with the lubricants and compression into tablets.
Indian patent 186250 describes a process for the preparation of tablet or capsule containing a drug, sodium alginate, xanthun gum, sodium bicarbonate and cross-linked poly vinyl pyrollidone. It was evident from the example stated by the author for dry granulation using roll compactor that the said drug as such is not suitable for tablet making. The method used in said patent as described is dry blending and roll compaction whereas the most preferred method of granulation is wet granulation. The granules obtained by wet granulation have better properties for the tableting behavior. Use of roll compaction is a lengthier process and adopted as a last option compared to wet granulation, which is capable of producing a large batch size in a limited period of time. The formula mentioned in this patent contains a quantity of the active pharmaceutical ingredient upto 69.9 % w/w that gives the tablet of 1000 mg drug of a very big size that may cause difficulty in swallowing.
United States patent US 2001/0018070A1 discloses the use of polyethylene oxide as an excipient for developing a formulation that extends the

release of the drug in the stomach during the fed mode by swelling to an extent that prevents the dosage form from passing through the pylorus.
The present application uses a novel combination of swelling and floating dosage form of ciprofloxacin using excipients to a minimum.
Drugs like, ciprofloxacin being a very low density material with poor flow properties needs superior granulation in order to achieve better flow and compaction properties. The granules obtained by wet granulation have better properties for tableting.
Wet granulation is the process in which a liquid is added to a powder in a vessel equipped with any type of agitation that will produce agglomeration or granules. The advantages of wet granulation method over dry granulation or compaction are as follows:
1. Drugs having a high dose and poor flow (like in case of ciprofloxacin) will require less binder to impart adequate compressibility and desired flow if wet granulated. In case of dry binding the quantity of binder will be very high to achieve the same properties for the granules.
2. In wet granulation bulky and dusty powders can be handled without producing a great deal of dust and airborne contamination.

3. Dry granulation can be practiced only by means of compaction .
For wet granulation there are many kind of methods. Moreover, in
dry granulation the lubricants usually used may deteriorate
disintegration and dissolution performance, tablet hardness and
drug stability.
4. Granules prepared by dry granulations are generally irregular or
plain, while these can be very many kinds of particle shape for
granules prepared by wet granulation.
5. In dry granulation and direct compression methods, compressibility
depends on the inherent deformation and cohesive properties of the
active substance and diluents. In wet granulation, distribution of
binders over the surface of the granules creates an adhesive
property in the material that makes up for the lack of cohesiveness
in the drugs and the diluents.
The object of the invention is to prepare an improved controlled release oral dosage composition as a once a day formulation for drugs like ciprofloxacin.
Another object of the invention is allowing for incorporation of a higher percentage by weight of the drug in the composition.

Still another object of the invention is for allowing for an oral dosage form which is small and convenient for oral administration.
Yet another object of the invention is to provide a once a day ciprofloxacin formulation having most optimum release profile when administered.
The present efforts are directed to a process to develop a gastric retentive dosage form with the following unique features.
1) Compressible to a size suitable for per-oral administration to humans
and also suitable for high dose drugs.
2) Retained for extended period in stomach due to expansion of dosage
form to a size that will prevent its passage through pylorus.
3) Entrapped air in hydro gel matrix causes the tablet to float on gastric fluid
thus gastric retention is achieved via dual mechanism.
4) Provides sustained and controlled release of drug for a period that is more or
less same as retention time of dosage form in stomach.
5) Monolithic device maintains structural integrity and sh ape memory even in
hydrated state and thus resist the housekeeper wave of IMMC.

6) Releases drug into stomach in solution phase rather than a solid phase
thus avoiding any chance of dose dumping.
7) Variation in drug release among dosage units is reduced to minimum.
The present invention provides for the preparation of a pharmaceutical composition in the form of controlled release once a day formulation comprising ciprofloxacin (78-84% w/w) as active ingredient; an in-situ gas forming agent,such as herein described, capable of producing a non-toxic gas upon contact with the gastric fluid (5-10% w/w); poly (ethylene oxide) (1-6% w/w) as a swellable polymer capable of entrapping the gas so generated and optionally having a fast dissolving film forming coating for tablet formulations and auxiliary pharmaceutically acceptable excipients, such as herein described, wherein the said process comprises the steps of-
a) binding ciprofloxacin with a solution (aqueous or organic solvent or a
mixture of both) of copolyvidone and kneading the same to obtain wet
mass;
b) drying the wet mass in a fluidized bed dryer and sizing them to form
ciprofloxacin drug granules;
c) binding sodium bi-carbonate with solution of povidone in isopropyl
alcohol and drying in a fluidized bed dryer to form sodium bicarbonate
granules;
d) mixing the Ciprofloxacin drug granules from step (b) with poly (ethylene
oxide) and sodium bi-carbonate granules from step (c), while lubricating
with magnesium stearate and colloidal silicon di-oxide
e) compressing the material from step (d) to tablets with suitable dies and
punches or encapsulating the material from step (d) into capsules by
conventional method and
f) optionally admixing with one or auxiliary excipents in step (d) above
and/or coating the tablets from step (e) by using a combination of lactose
talc and titanium dioxide as the coating .
The present invention further provides a process for the preparation of a pharmaceutical composition in the form of controlled release once a day

formulation comprising ciprofloxacin (78-84% wAv) as active ingredient; an in-situ gas forming agent,such as herein described capable of producing a nontoxic gas upon contact with the gastric fluid (5-10% w/w); hydroxypropyl methyl cellulose (5-12% w/w) as a swellable polymer capable of entrapping the gas so generated and optionally having a fast dissolving film forming coating for tablet formulations and auxiliary pharmaceutically acceptable excipients, such as herein described, wherein the said process comprises the steps of-
a) binding ciprofloxacin with a solution (aqueous or organic solvent
or a mixture of both) of copolyvidone and kneading the same to
obtain wet mass;
b) drying the wet mass in a fluidized bed dryer and sizing them to
form ciprofloxacin drug granules;
c) binding sodium bi-carbonate with solution of povidone in
isopropyl alcohol and drying in a fluidized bed dryer to form
sodium bi-carbonate granules;
d) mixing the ciprofloxacin drug granules from step (b) with
hydroxypropyl methyl cellulose and sodium bi-carbonate granules
from step (c), while lubricating with magnesium stearate and
colloidal silicon di-oxide
e) compressing the material from step (d) to tablets with suitable dies
and punches or encapsulating the material from step (d) into a
capsule by conventional method and
f) optionally admixing with one or auxiliary excipents in step (d)
above and/or coating the tablets from step (e) by using a
combination of lactose talc and titanium dioxide as the coating .
Brief description of the Accompanying Drawings
Figure 1 gives Mean Plasma Concentration vs. time curve for test formation according to the present invention i.e. Ciprofloxacin 1000 mg OD (bio-availability
study).
9A

Controlled release devices of invention find use in humans or other animals. Additionally, gastro retentive system according to present invention can be used effectively in administration of a drug that can be used in local treatment of ailments like H.Pylori infection.
The composition of the present invention is most suitable for once a day formulation of ciprofloxacin although it can also be used for other drug of similar solubility in the gastric fluid and exhibiting such absorption window.
Ciprofloxacin is a fluoroquinolone and one of the earliest drugs of this group that is widely used. It is effective against most of the common organisms which include gram negative organisms like Pseudomonas aeruginosa, Escherichia coli, Salmonella typhi, Klebsiella pneumoniae, Haemophillus influenzae, Shigella and gram positive organisms like Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus pneumoniae and Streptococcal pyrogenes. One of the aspects in ensuring the effectiveness of any drug therapy is convenience of administration leading to a better compliance.
The present invention provides an improved controlled release oral dosage composition as a once a day formulation wherein said composition comprising a pharmaceutical ingredient or a drug like Ciprofloxacin, an in-situ gas-forming agent capable of producing nontoxic gas upon contact with the gastric content, a highly swellable polymer capable of entrapping the generated gas, and optional fast dissolving film-forming coating with a pharmaceutical excipient.
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The insitu gas generating agent may be selected from, but not limited to sodium bicarbonate, calcium carbonate, magnesium carbonate, sodium sulfite and the like.
The highly swellable polymer may be selected from poly (ethylene oxide) and hydroxypropyl methylcellulose.
As indicated above the composition according to the present invention may comprise auxiliary excipients such as binder, lubricants and the like.
The suitable binder can be selected from, but not limited to povidone, copolyvidone, hydroxypropylmethylcellulose and the like.
The lubricant can be selected from, but not limited to talc, colloidal silicon dioxide, magnesium stearate and the like.
The ingredients like lactose, talc, titanium dioxide can be used to form coating on the tablet.
It has been further observed by the inventor of the present invention, that most optimum dissolution profile of the drug with release of 20-60% of the drug within first hour, 40-80% of the drug within first two hours and not less than 85% of the drug within eight hours of administration is exhibited when the weight ratio of the rate controlling swellable polymer namely poly ethylene oxide and hydroxy propyl methyl cellulose used in the said formation is kept within certain range, particularly with range of weight ratio of 1 to 6% w/w
11

and more preferably 2 to 5% w/w for polyethylene oxide and range of weight ratio of 5 to 12% w/w and more preferably from 7.5 to 12% w/w hydroxy propyl methyl cellulose.
The extent of drug that could be included in the formulation is 78-84% w/w. Thus, the controlled release oral dosage composition of the instant invention made by wet granulation method helps in high drug loading with high percentage by weight of the drug in the composition not achieved by the prior art composition. Further, the oral dosage form is small and convenient for oral administration with a highly satisfactory release profile.
The examples given herein are by way of illustration alone and in no way limit the scope of the invention.
Example -1
A typical example according to the present invention is given in Table 1:
Table 1:

Sr. No. Ingredients Weight (mg / tablet) % w/w
1. Ciprofloxacin base 1000.00 83.19
2. Copolyvidon 30.00 2.50
3. Poly (ethylene oxide) WSR N303 40.00 3.33
4. Sodium bi-carbonate 100.00 8.32
5. Povidone 5.00 0.42
6. Magnesium Stearate 20.00 1.66
7. Colloidal silicon di-oxide 7.00 0.58
Total 1202.00 100.00
12

The process for the preparation of the pharmaceutical composition according to the present invention will now be described in more detail.
The active pharmaceutical ingredient was bound with a solution (aqueous or organic solvent or a mixture of both) of Copolyvidone and kneaded to obtain wet mass. The granules were dried in a fluidized bed dryer. The dried granules were sized. Sodium bi-carbonate was binded with solution of Povidone in Isopropyl alcohol and dried in a fluidized bed dryer.
Ciprofloxacin drug granules were mixed with poly (ethylene oxide) and sodium bi-carbonate granules, lubricated with magnesium stearate, colloidal silicon di-oxide and compressed to tablets with suitable dies and punches. The tablets were coated to avoid the bitter taste with the composition as given in the Table 2.
Table 2:

Sr. No. Ingredients Weight (mg / tablet) % w/w
1. Lactose 12.93 71.68
2. Talc 2.92 16.18
3. Titanium di-oxide 2.17 12.14
4. Water q.s -
Total 18.02 100.00
13

The tablets were tested for dissolution in 900 ml of 0.1 N HC1 with basket in USP at 100 rpm in Dissolution apparatus and the results are tabulated in the Table 3.
Table 3:

Time (hrs) Cumulative percent release
1 35.20
2 53.15
4 75.27
6 97.20
Example - 2
The composition is given in Table-4
Table 4:

SR. NO. Ingredients Weight (mg/tablet) %w/w
1. Ciprofloxacin base 1000.00 78.13
2. Hydroxypropylmethylcellulose (15cps) 15.00 1.17
3. Hydroxypropylmethylcellulose (K4M) 135.00 10.55
4. Sodium bi-carbonate 100.00 7.81
5. Povidone 5.00 0.39
6. Magnesium Stearate 20.00 1.56
7. Colloidal silicon di-oxide 5.00 0.39
Total 1280.00 100.00
The active pharmaceutical ingredient was bound with a solution (aqueous or organic solvent or a mixture of both) of Hydroxypropylmethylcellulose (15 cps) and kneaded to obtain wet mass. The granules were dried in a fluidized bed
14

dryer. The dried granules were sized. Sodium bi-carbonate was binded with solution of Povidone in Isopropyl alcohol and dried in a fluidized bed dryer. Ciprofloxacin drug granules were mixed with Hydroxypropylmethylcellulose (K4M) and sodium bi-carbonate granules, lubricated with magnesium stearate, colloidal silicon di-oxide and compressed to tablets with suitable dies and punches. The tablets were coated as described in Example 1.
The tablets are tested for dissolution in 900 ml. of 0.1 NHC1 with basket in USP at 100 rpm. in Dissolution apparatus and the results are tabulated in the Table 5.
Table 5:

Time (hrs) Cumulative percent release
1 21.7
2 42.1
8 99.73
Example - 3 (for Capsule)
The composition is given in Table - 6
Table 6:
SR. NO. Ingredients Weight (mg/capsule) %W/W
1. Ciprofloxacin base 500.00 82.85
2. Copolyvidon 15.00 2.49
3. Polyethylene oxide) WSR N303 22.5 3.73
4. Sodium bi-carbonate 50.00 8.28
5 Povidone 2.5 0.41
6 Magnesium Stearate 10 1.66
___7 Colloidal silicon di-oxide 3.5 0.58
Total 603.5 100.00
15

The granules of Ciprofloxacin are prepared as per the method given in example 1. The granules equivalent to 500 mg are filled in hard gelatin capsule shell.
The capsules are tested for dissolution in 900 ml of 0.1 NHC1 with basket in USP at 100 rpm in Dissolution apparatus and the results are tabulated in the Table 7.
Table 7:

Time (hrs) Cumulative percent release
1 53.42
2 74.67
8 97.71
The composition of Examples 1-3 according to the present invention thus satisfy the range of dissolution profile for such one a day formulation as given below :-
Table 8

Time (hrs) % Ciprofloxacin released
1 20% to 60%
2 40% to 80%
8 Not less than 85%
In order to find out most optimum range of weight ratio of the rate controlling polymer in the composition further experiments were conducted as described below :-
16

A. with higher quantity of polymer viz Hydroxypropyl methyl cellulose
and same amount of the active ingredient viz. ciprofloxacin (Example
4).
B. with higher quantity of polymer viz. poly (ethylene oxide) and same
amount of the active ingredient viz. ciprofloxacin (Example 5).
C. with low quantity of the polymer viz poly (ethylene oxide) and same
amount of the active ingredient viz ciprofloxacin (Example 6)
Example 4
Experiment with high quantity of polymer (Hydroxypropyl methyl cellulose (HPMC)) :
Objective:
This experiment has been carried out in the same manner as given in example 2 above where rate controlling polymer namely Hydroxypropyl methyl cellulose (K 4M) (HPMC) used is 135mg/tablet. The only difference is the high quantity of polymer hydroxypropyl methyl cellulose (HPMC)(175 mg/tablet) used in this experiment. The composition is given below :-
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Table 9

Sr. No. Ingredients Weight (mg/tablet) %w/w
I Ciprofloxacin base 1000.00 75.76
2 (Hydroxypropylmethylcellulose (15cps) 15.00 1.13
3 Hydroxypropylmethylcellulose
(K4M) 175.00 13.26
4 Sodium bi-carbonate 100.00 7.58
5 Povidone 5.00 0.38
6 Magnesium Stearate 20.00 1.51
7 Colloidal silicon di-oxide 5.00 0.38
Total 1320.00 100.00
Method : Same as given in example 2 above .
Result and analysis :
The tablets are tested for dissolution in 900 ml of 0.1 N HC1 with basket in USP at 100 rprh in Dissolution apparatus and the results are tabulated in the table given below :-
Table 10

Time (hrs.) Cumulative percent release
1 19.5
2 32.46
8 97.9
The cumulative percent release at the end of 2 hours is 32.46 (limit 40%-80%, refer Table 8), hence, the dissolution profile is not satisfactory.
18

Example 5
Experiment with high quantity of polymer (polyethylene oxide) :
Objective :
This experiment has been carried out in the same manner as given in example 1 above where rate controlling polymer namely Poly (ethylene oxide) (WSR N303) used is 40 mg/tablet. The only difference is the higher quantity of said polymer (100 mg/tablet) used in this experiment. The composition is given below :-
Table 11

Sr. No. [ngredients Weight (mg/tablet) %w/w
1 Ciprofloxacin base 1000.00 79.36
2 Copolyvidone 30.00 2.38
3 Poly (ethylene oxide) (WSR N303) 100.00 7.94
4 Sodium bi-carbonate 100.00 7.94
5 Povidone 5.00 0.39
6 Magnesium Sterate 20.00 1.59
7 Colloidal Silicon Dioxide 5.00 0.40
Total 1260.00 100.00
Method : Same as given in example 1 above. Result and analysis :
The tablets are tested for dissolution in 900 ml of 0.1 N HC1 with basket in USP at 100 rpm in Dissolution apparatus and the results are tabulated in the table given below :-
19

Table 12

Time (hrs.) Cumulative percent release
1 15.21
2 24.7
8 64.57
The cumulative percent release at the end of 1 hour is 15.21 (limit 20%-60%, refer Table-8), at the end of 2 hours, it is 24.72 (limit -40%-80%, refer Table-8), hence the results of dissolution profile are not satisfactory.
Example 6
Experiment with low quantity of polymer namely Poly (ethylene oxide)(WSR
N303):
Objective
This experiment has been carried out in the same manner as given in example 1
above, where rate controlling polymer namely Poly (ethylene oxide) (WSR
N303) used is 40 mg/tablet. The only difference is the low quantity (5 mg/tablet)
of said polymer used in this experiment.
The composition is as given below :
Table 13

Sr. No. Ingredients Weight (mg/tablet) %w/w
1 Ciprofloxacin base 1000.00 85.83
2 Copolyvidone 30.00 2.58
3 Poly (ethylene oxide) (WSRN303) 5.00 0.43
4 Sodium bi-carbonate 100.00 8.58
5 Povidone 5.00 0.43
6 Magnesium Stearate 20.00 1.72
7 Colloidal Silicon Dioxide 5.00 0.43
Total 1165.00 100.00
20

Method : Same as given in example 1. Results and analysis :
The tablets are tested for dissolution in 900 ml of 0.1 NHC1 with basket in USP at 100 rpm in Dissolution apparatus and the results are tabulated in the table given below :
Table 14

Time (hrs) Cumulative percent release
1 90.6
2 96
4 100.1
The cumulative percent release at the end of 1 hour is 90.6 (limit 20%-60%, refer Table - 8), at the end of 2 hours, it is 96 (limit 40%-80%, refer Table-8) and at the end of 4 hrs, 100.1 (limit not less than 85% in 8 hours, refer Table-8), hence, the results of dissolution profile are not satisfactory.
21

Conclusion:
The experiments were conducted with high and low quantity of polymer. In order to comply with the in vitro results, the dissolution profile should be well within the range of all the three limits indicated in Table 8. As one or more of the in vitro dissolution results of the experiments i.e. Example 4, Example 5 and Example 6 are outside the limits specified in Table 8, none of them provide a satisfactory release profile for the drug, indicating that the composition mentioned in the invention is very critical for an efficacy of administered drug. Accordingy when Hydroxypropyl methyl cellulose (HPMC) is used as the rate controlling polymer the range of weight ratio of this polymer should preferably be 5 to 12% w/w and most preferably 7.5 to 12% w/w. In case of poly (ethylene oxide) as the rate controlling polymer, the weight ratio of the polymer is preferably 1 to 6% w/w and most preferably 2 to 5% w/w.
Biological activity of the tablets prepared according to the instant invention was studied. Efficacy was further studied and correlated with blood level of the drugs and the areas under plasma concentration vs. time curve as shown in Fig. 1 of the drawing.
Once a day formulation of Ciprofloxacin is designed with a view to achieve the compliance to the treatment without affecting the therapeutic
22

efficacy. In a bioavailability study in 12 healthy male volunteers, the drug was administered as one tablet of l000mg in a fed state. The blood samples were drawn for a period of 24 hours and were measured by HPLC method. The mean of AUC (Area Under the Curve) when computed is well above the required MIC (Minimum Inhibitory Concentration) for majority of the organisms. This concentration above MIC is for a period of upto 18 hrs. This duration along with the post antibiotic effect, a known phenomenon of antibiotic effects is adequate to provide an antibiotic cover to the patient for a period of 24 hrs.
The results of this study are as under :-

OD : Once a day
Area Under the Curve (AUC) - The integral part of drug blood level over time from zero to infinity and is a measure of quantity of drug absorbed and in the body.
AUC(o-t) - Area under the curve from zero to time t, where t represents the time at which last blood sample was taken.
AUC - Area under the curve from zero to infinity.
23

t½ (Elimination half life of a drug) - The time in hours necessary to reduce the drug concentration in the blood, plasma or serum to ½(half) after equilibrium is reached.
Cmax - The peak plasma concentration achieved after the administration of the
drug.
Tmax - The time to reach peak plasma concentration.
As shown in Fig. 1, the curve of the test product according to the invention [OD-l000mg) has serum concentration up to 0.5 gm/ml till 18 hours and above 0.06 gm/ml till 24 hours. These values cover most of the microorganisms for a period enough to extend post-antibiotic effect i.e. letting the body's defense cells take care of reduced bacterial load. Thus, the formulation according to the instant invention indicates that it is suitable as once a day formulation.
24

We claim:
1. A process for the preparation of a pharmaceutical composition in the form of controlled release once a day formulation comprising ciprofloxacin (78-84% w/w) as active ingredient; an in-situ gas forming agent,such as herein described, capable of producing a non-toxic gas upon contact with the gastric fluid (5-10% w/w); poly (ethylene oxide) (1-6% w/w) as a swellable polymer capable of entrapping the gas so generated and optionally having a fast dissolving film forming coating for tablet formulations and auxiliary pharmaceutically acceptable excipients, such as herein described, wherein the said process comprises the steps of-
a) binding ciprofloxacin with a solution (aqueous or organic solvent or a
mixture of both) of copolyvidone and kneading the same to obtain wet
mass;
b) drying the wet mass in a fluidized bed dryer and sizing them to form
ciprofloxacin drug granules;
c) binding sodium bi-carbonate with solution of povidone in isopropyl
alcohol and drying in a fluidized bed dryer to form sodium bi-carbonate
granules;
d) mixing the Ciprofloxacin drug granules from step (b) with poly
(ethylene oxide) and sodium bi-carbonate granules from step (c), while
lubricating with magnesium stearate and colloidal silicon di-oxide
e) compressing the material from step (d) to tablets with suitable dies and
punches or encapsulating the material from step (d) into capsules by
conventional method and
f) optionally admixing with one or auxiliary excipents in step (d) above
and/or coating the tablets from step (e) by using a combination of
lactose talc and titanium dioxide as the coating .
2. A process for the preparation of a pharmaceutical composition in the form of controlled release once a day formulation comprising ciprofloxacin (78-84% w/w) as active ingredient; an in-situ gas forming agent,such as herein described capable of producing a non-toxic gas upon contact with the gastric fluid (5-10% w/w); hydroxypropyl methyl cellulose (5-12% w/w) as a swellable polymer capable of entrapping the gas so generated and optionally having a fast
25

dissolving film forming coating for tablet formulations and auxiliary pharmaceutically acceptable excipients, such as herein described, wherein the said process comprises the steps of-
a) binding ciprofloxacin with a solution (aqueous or organic solvent
or a mixture of both) of copolyvidone and kneading the same to
obtain wet mass;
b) drying the wet mass in a fluidized bed dryer and sizing them to
form ciprofloxacin drug granules;
c) binding sodium bi-carbonate with solution of povidone in
isopropyl alcohol and drying in a fluidized bed dryer to form
sodium bi-carbonate granules;
d) mixing the ciprofloxacin drug granules from step (b) with
hydroxypropyl methyl cellulose and sodium bi-carbonate
granules from step (c), while lubricating with magnesium stearate
and colloidal silicon di-oxide
e) compressing the material from step (d) to tablets with suitable
dies and punches or encapsulating the material from step (d) into
a capsule by conventional method and
f) optionally admixing with one or auxiliary excipents in step (d)
above and/or coating the tablets from step (e) by using a
combination of lactose talc and titanium dioxide as the coating .
3. A process as claimed in claim 1 or 2, wherein said gas forming agent is
selected from sodium bi-carbonate, calcium carbonate, magnesium
carbonate or sodium sulflte.
4. A process as claimed in claim lor 2 , wherein the formulation is in the
form of tablet.
5. A process as claimed in claim lor 2 , wherein the formulation is in the
form of capsule.
6. A process as claimed in claims 1 or 2 , wherein talc is used as an auxiliary
excepient in the form of a lubricant.
26

7. A process as claimed in claims lor 2, wherein a combination of lactose,
talc and titanium dioxide is used for applying a coating on the formulation made as tablets has the following composition:

Sr. No. Ingredients Weight (mg / tablet) % w/w
1. Lactose 12.93 71.68
2. Talc 2.92 16.18
3. Titanium di-oxide 2.17 12.14
4. Water q.s -
Total 18.02 100.00
8. A process as claimed in claim lor 2, wherein the formulation in the
form of tablet is made by the wet granulation process.
9. A process as claimed in claims 1 , wherein polyethylene oxide is
used as the polymer component in the weight ratio of 2 to 5% w/w.
10. A process as claimed in 2, wherein hydroxypropyl methylcellulose is
used as the polymer component in the weight ratio of 7.5 to 12%
w/w.
11. A process as claimed in claim 1,wherein the ingredients of the
formulation are present in the following proportion: -

Ingredients
1. Ciprofloxacin base
2. Copolyvidon
3. Poly (ethylene oxide) WSR N303
4. Sodium bi-carbonate
5. Povidone
6. Magnesium Stearate
7. Colloidal silicon di-oxide


Weight % w/w
(mg / tablet)
1000.00 83.19
30.00 2.49
40.00 3.33
100.00 8.32
5.00 0.42
20.00 1.66
7.00 0.58

27

12. A process as claimed in claim 2, wherein the ingredients of the formulation are present in the following proportion: -

Ingredients
1 Ciprofloxacin base
2 Hydroxypropylmethylcellulose (15cps)
3 Hydroxypropylmethylcellulose (K4M)
4 Sodium bi-carbonate
5 Povidone
6 Magnesium Stearate
.7 Colloidal silicon di-oxide


Weight % wA
(mg/tablet)
1000.00 78.13
15.00 1.17
135.00 10.55
100.00 7.81
5.00 0.39
20.00 1.56
5.00 0.39

13. A process as claimed in claim 1 , wherein the ingredients of the formulation are present in the following proportion :-

Ingredients Weight %w/v
(mg/capsule)
1 .Ciprofoxacin base 500.00 82.85
2. Copolyvidone 15.00 2.49
3. Poly(ethyleneoxide) WSRN30 22.50 3.73
4. Sodium bi-carbonate 50.00 8.29
5. Povidone 2.50 0.41
6. Magnesium Stearate 10.00 1.66
7. Colloidal silicon di-oxide 3.50 0.58
28

14. A process for preparation of coated tablets as claimed in claim 1 or 2, wherein the coating composition is as follows:

Ingredients Weight %w/w
(mg/tablet)
1. Lactose 100.00 71.42
2. Talc 75.00 5.35
3. Titanium di-oxide 30.00 2.14
4. Water q.s
A process as claimed in any of the preceding claims for preparation of tablets, wherein ciprofloxacin that exhibits the following in-vitro dissolution profile when measured in a type 1 dissolution apparatus (Basket) according to USP XXIV at 37oC in 900 ml of 0.1 N Hydrochloric acid at 100 rotations per minute.
Time in Hrs. % Ciprofloxacin released
1 20% to 60%
2 40% to 80%
8 Not less than 85%
16. A process for the preparation of pharmaceutical composition substantially herein described particularly with reference to the examples.
15.

29
The present invention discloses a process for the preparation of pharmaceutical composition in the form of controlled release once a day formulation comprising an active ingredient such as ciprofloxacin (78-84% w/w); an in-situ gas forming agent (5-10% w/w); a swellable polymer selected from hydroxypropyl methyl cellulose (5-12% w/w) or poly (ethylene oxide) (1-6% w/w) and optionally having a fast dissolving film forming coating and an auxiliary pharmaceutically acceptable excepient comprising the steps of (a) binding ciprofloxacin with a solution of copolyvidone or hydroxy propylmethyl cellulose and kneading the same to form a wet mass (b) drying and sizing the wet mass to form ciprfloxacin drug granules (c ) binding sodium bi-carbonate with solution of providone in isopropyl alcohol and drying the same in a fluidized bed dryer to get sodium bi-carbonate granules (d) mixing the ciprofloxacin with poly(ethylene oxide) or hydroxy propylmethyl cellulose and sodium bi-carbonate granules thus obtained with lubricants (e) compressing into tablets and coating the same.

Documents:


Patent Number 202520
Indian Patent Application Number 24/KOL/2004
PG Journal Number 10/2007
Publication Date 09-Mar-2007
Grant Date 09-Mar-2007
Date of Filing 16-Jan-2004
Name of Patentee TORRENT PHARMACEUTICALS LTD.
Applicant Address CENTRAL PLAZA, 1ST FLOOR, ROOM # -106, 2/6 SARAT BOSE ROAD, CALCUTTA
Inventors:
# Inventor's Name Inventor's Address
1 VYAS SHARAD KUMAR B/31, GOYAL PARK APARTMENT, OPPOSITE LAD SOCIETY, VASTRAPUR, AHMEDABAD 380 015, GUJARAT
PCT International Classification Number A 61 K 9/00
PCT International Application Number N/A
PCT International Filing date
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 NA