Claims:Claims
We claim:
1. A floating pulsatile drug delivery system comprising a composition comprising a three component system wherein at least two components out of the three contained an H2 receptor antagonist.
2. The floating pulsatile drug delivery system of claim 1 wherein at least two components out of the three contained at least one release controlling agent.
3. The floating pulsatile drug delivery system of claim 1 wherein three components are an immediate release section, an extended release section and a coating having at least one release controlling agent.
4. The floating pulsatile drug delivery system of claim 3 wherein the extended release section has at least two release controlling agents.
5. A floating pulsatile drug delivery system comprising a coated inlay tablet comprising three components wherein at least two components out of the three contained at least one H2 receptor antagonist.
6. The floating pulsatile drug delivery system of claim 5 wherein at least two components out of the three contained at least one release controlling agent.
7. The floating pulsatile drug delivery system of claim 5 wherein three components are an immediate release section, an extended release section and a coating having at least one release controlling agent.
8. The floating pulsatile drug delivery system of claim 5 wherein the extended release section has at least two release controlling agents.
9. A floating pulsatile drug delivery system comprising a composition of Ranitidine comprising a three component system and exhibiting following in vitro release profile in water media
i. not more than 10 % in 4 hrs
ii. not more than 60 % at the end of 8 hrs
iii. not more than 90 % at the end of 12 hrs, preferably not more than 80 % at the end of 12 hrs
10. The floating pulsatile drug delivery system according to claim 9 exhibiting following in vitro release profile for Ranitidine in water media
i. not more than 10 % in 4 hrs
ii. not more than 50 % in 8 hrs
iii. not more than 80 % at the end of 12 hrs.
11. A floating pulsatile drug delivery system comprising a coated inlay tablet comprising a three component system wherein at least two components out of the three contained at least one H2 receptor antagonist and wherein at least two components out of the three contained at least one release controlling agent.
12. The floating pulsatile drug delivery system of claim 11 wherein three components are an immediate release section, an extended release section and a coating having at least one release controlling agent and wherein the extended release section has at least two release controlling agents.
13. The floating pulsatile drug delivery system of claim 12 comprising Ranitidine as H2 receptor antagonist and exhibiting following in vitro release profile in water media
i. not more than 10 % in 4 hrs, preferably not more than 10 % in 6 hrs,
ii. not more than 60 % at the end of 8 hrs,
iii. not more than 90 % at the end of 12 hrs, preferably not more than 80
% at the end of 12 hrs
14. The floating pulsatile drug delivery system of claim 12 wherein a release controlling agent is selected from the group consisting of hydrophilic and hydrophobic components.
15. The floating pulsatile drug delivery system of claim 14 wherein hydrophilic components is selected from one or more of hydrophilic polymers, hydrophilic gums, hydrophilic polysaccharides and pH sensitive polymers.
16. The floating pulsatile drug delivery system of claim 12 wherein hydrophobic component is selected from one or more hydrophobic polymers.
17. A floating pulsatile drug delivery system comprising a composition comprising
(i) an internal phase comprising an H2 receptor antagonist, 1 – 7 % disintegrant and no or low amount of release controlling agent of total weight of composition
(ii) external phase comprising an H2 receptor antagonist and at least 20 % and preferably at least 25 % of one or more release controlling agents of total weight of composition,
(iii) coating comprising no H2 receptor antagonist and less than 20 % of release controlling agent of total weight of composition.
18. The floating pulsatile drug delivery system of claim 17 wherein ratio of H2 receptor antagonist in internal and external phase is from 5:1 to 1:5, preferably from 4:1 to 1:4 and most preferably from 3:1 to 1:3.
19. A process of preparing a floating pulsatile drug delivery system for pulsatile followed by an extended release of an H2 receptor antagonist comprising following steps
i) blending with part of the H2 receptor antagonist, one or more of diluent, disintegrant, binder to form a blend,
ii) blending with the blend of step i, one or more of lubricant and glidant to form lubricated blend,
iii) compressing the blend of step ii to form tablet,
iv) blending with the remaining part of H2 receptor antagonist, one or more of diluents, binder and at least one release controlling agent selected from the group of hydrophilic component which is selected from one or more of hydrophilic polymers, hydrophilic gums, hydrophilic polysaccharides and pH sensitive polymers and hydrophobic components to prepare blend,
v) compressing tablet of step iii and blend of step iv in an inlay tablet,
vi) coating the tablet of step v with coating material comprising one or more of hydrophilic polymer, hydrophobic polymer and pH sensitive polymer.
20. The process of preparing a floating pulsatile drug delivery system of claim 19 wherein ratio of active in step I and step iv is from 5:1 to 1:5, preferably from 4:1 to 1:4 and most preferably from 3:1 and 1:3.

Dated this…………..day of ……………………………2016.

Ms. KHARKAR PALLAVI SHASHIKANT
Patent Agent Registration No. IN/PA-1138
(Agent for the Applicants)
, Description:Field of Invention
The present invention covers pulsatile and extended release compositions of H2 receptor antagonists particularly Ranitidine. The compositions provide release in pulsatile manner in the beginning and extended manner after initial pulsed quantity of H2 receptor antagonists particularly Ranitidine is released. It prolongs release such that H2 receptor antagonists particularly Ranitidine is released over 24 hours following a particular pattern which is characterized by its release from 0 – 24 hrs.
Background of Invention
US20150079170A1 covers a bilayered tablet dosage form comprising:
a first layer having inert excipients; and a second layer comprising one or more active pharmaceutical ingredients and optionally other pharmaceutically acceptable excipients, and an inlaid tablet comprising one or more active pharmaceutical ingredients, wherein the inlaid tablet is coated with a seal coating layer comprising one or more seal coat polymers followed by enteric coating with enteric polymer. This dosage form can’t provide pulsatile and extended release together.
US20080317846 provides a histamine H2 antagonist pharmaceutical dosage form
providing a bi-modal pulsatile release profile comprising: a. immediate release (IR) beads and b. timed pulsatile release (TPR) beads. Such form does not provide release of actives over 24 hrs.
US8920837B2 covers a sustained-release oral dosage form comprising,
a. therapeutically effective amount of a pharmacologically active ingredient having aqueous solubility of greater than 1 mg/ml,
b. at least one non-swelling pH dependent, release retardant in an amount from about 10 to about 90% by weight of the total composition, and
c. at least one non-swelling pH independent, release-retardant in an amount from about 10 to about 90% by weight of the total composition,
wherein the dosage form provides pH independent drug release for a considerable period of time after administration, and the dosage form is a matrix dosage form. This dosage form requires large amount of release retardant and not suitable for actives having high dose.
Summary of Invention
In a first aspect, the present invention provides a floating pulsatile drug delivery system that provides a pulsatile and an extended release composition of an active ingredient, particularly, H2 receptor antagonists including without limitation cimetidine, famotidine, nizatidine and ranitidine, and most particularly, Ranitidine.
However this technology can be applied to any active wherein one part of dosage is needed to be administered in pulsed form and the second part of dose is needed to be administered over an extended period.
The active agents that may be administered using a floating pulsatile drug delivery system of the present invention are not limited, as the invention enables the effective delivery of a wide variety of active agents. This technology can be applied to any active wherein one part of dosage is needed to be administered in pulsed form within 8 hrs from administration and the second part of dose is needed to be administered over an extended period from 8 – 24 hrs. To enable this type of release, floating pulsatile drug delivery system comprises a composition having three sections. It is not necessary that only Ranitidine in one section would be released in pulsatile manner and Ranitidine in other section would be released in an extended manner. Overlap is possible such that some Ranitidine in pulsatile section may be released in extended manner and some Ranitidine in extended portion may be released in 6-8 hrs. However major pulsatile release is contributed by the Ranitidine in pulsatile section and major extended release is contributed by the Ranitidine in an extended section.
Any reference to term Ranitidine includes any salt, solvate, hydrate, crystal form or derivative of ranitidine. The term Ranitidine and Ranitidine hydrochloride are used synonymously and when it is said that Ranitidine is a highly soluble drug, it is understood to mean that inventors talk about hydrochloride salt of Ranitidine which is highly soluble.
The active agents administered using a floating pulsatile drug delivery system of the present invention may be selected from any of the various classes of such agents including, but not limited to, analgesic agents, anesthetic agents, anti-anginal agents, antiarthritic agents, anti-arrhythmic agents, antiasthmatic agents, antibacterial agents, anti-BPH agents, anticancer agents, anticholinergic agents, anticoagulants, anticonvulsants, antidepressants, antidiabetic agents, antidiarrheals, anti-epileptic agents, antifungal agents, antigout agents, antihelminthic agents, antihistamines, antihypertensive agents, antiinflammatory agents, antimalarial agents, antimigraine agents, antimuscarinic agents, antinauseants, antineoplastic agents, anti-obesity agents, antiosteoporosis agents, antiparkinsonism agents, antiprotozoal agents, antipruritics, antipsychotic agents, antipyretics, antispasmodics, antithyroid agents, antitubercular agents, antiulcer agents, anti-urinary incontinence agents, antiviral agents, anxiolytics, appetite suppressants, attention deficit disorder (ADD) and attention deficit hyperactivity disorder (ADHD) drugs, calcium channel blockers, cardiac inotropic agents, beta-blockers, central nervous system stimulants, cognition enhancers, corticosteroids, COX-2 inhibitors, decongestants, diuretics, gastrointestinal agents, genetic materials, histamine receptor antagonists, hormonolytics, hypnotics, hypoglycemic agents, immunosuppressants, keratolytics, leukotriene inhibitors, lipid-regulating agents, macrolides, mitotic inhibitors, muscle relaxants, narcotic antagonists, neuroleptic agents, nicotine, nutritional oils, parasympatholytic agents, sedatives, sex hormones, sympathomimetic agents, tranquilizers, vasodilators, vitamins, and combinations thereof. Active agents that may be administered according to the invention also include nutrients, cosmeceuticals, diagnostic agents, and nutritional agents. Some agents, as will be appreciated by those of ordinary skill in the art, and as may be deduced from the discussion below, are encompassed by two or more of the aforementioned groups.
The actives which fall in above therapeutic category may differ in their properties for example they may have different solubility pattern. The present invention provides a floating pulsatile drug delivery system such that an extended release section thereof may have at least one release controlling agent such that for more soluble actives, either high concentrations of release controlling agent or combination of two or more release controlling agent or both strategies can be applied.
In accordance with the present invention, the dose of H2 receptor antagonists particularly Ranitidine is divided in two parts such that a part of the active exhibits a pulsed release and the remaining part exhibits an extended release. Such composition provides release of H2 receptor antagonists particularly Ranitidine over 24 hours.
In a second aspect, the present invention provides a coated inlay tablet composition of any active ingredient, particularly H2 receptor antagonists and most particularly Ranitidine or tablet in tablet composition of any active ingredient, particularly H2 receptor antagonists particularly Ranitidine which is further coated. Such coated inlay tablet has three sections, an inner section or inner phase, an outer section or outer phase and a coating section. Both the external and internal phases of the inlay tablet contains H2 receptor antagonists particularly Ranitidine. The inlay tablet is coated with a coating containing at least one excipient that modifies or controls release of H2 receptor antagonists particularly Ranitidine.
The coating can be either a single coating having one or more release controlling agent or two or more coatings each having one or more release controlling agent. When two coatings are used, at least one release controlling agent in both the coatings is preferably different. Coating material may have apart from release controlling agent, plasticizer, talc and any other conventional ingredient.
The other excipients in external and internal phases comprises one or more of diluent, binder, disintegrant, glidant and lubricant. The external phase contains at least one release controlling agent and preferably two or more release controlling agents. Internal phase is an immediate release composition containing no or low amounts of release controlling agent.
In a third aspect, the present invention covers a composition of H2 receptor antagonists particularly Ranitidine having following release pattern
not more than 10 % in 4 hrs, preferably not more than 10 % in 6 hrs,
not more than 60 %, preferably not more than 50 % in 8 hrs,
not more than 90 % at the end of 12 hrs, preferably not more than 80 % at the end of 12 hrs.

Detailed description of the invention
Ranitidine has been prescribed for various indications. The indications and the prescribed dosage is as follows:
Sr. No. Indications Dosage (adult)
1 Duodenal Ulcer Oral: 150 mg 2 times a day, or 300 mg once a day after the evening meal or at bedtime.
Parenteral: 50 mg, IV or IM, every 6 to 8 hours. Alternatively, a continuous IV infusion may be administered at a rate of 6.25 mg/hour over 24 hours.
2 Dyspepsia 75 mg orally once daily (Over-the-counter) 30 to 60 minutes before meal. Dose may be increased to 75 mg twice daily. Maximum duration of therapy if self-medicating is 14 days.
3 Erosive Esophagitis Oral:
Initial: 150 mg 4 times a day.
Maintenance: 150 mg twice daily.
Parenteral: 50 mg, IV or IM, every 6 to 8 hours. Alternatively, a continuous IV infusion may be administered at a rate of 6.25 mg/hour over 24 hours.
4 Zollinger-Ellison Syndrome Oral: 150 mg 2 times a day initially. Adjust dose to control gastric acid secretion. Doses up to 6 g per day have been used.
Parenteral: 1 mg/kg/hour administered as a continuous IV infusion to a maximum of 2.5 mg/kg/hour (infusion rates up to 220 mg/hour have been used).
5 Hypersecretory Conditions Oral: 150 mg 2 times a day initially. Adjust dose to control gastric acid secretion. Doses up to 6 g per day have been used.
Parenteral: 1 mg/kg/hour administered as a continuous IV infusion to a maximum of 2.5 mg/kg/hour (infusion rates up to 220 mg/hour have been used).
6 Gastroesophageal Reflux Disease Oral: 150 mg twice daily.
Parenteral: 50 mg, IV or IM, every 6 to 8 hours.
7 Gastric Ulcer
Benign Gastric Ulcer Oral: 150 mg twice a day.
Parenteral: 50 mg, IV or IM, every 6 to 8 hours.
Indication Dosage (Pediatric Dose)
8 Duodenal Ulcer
1 month to 16 years:

IV: 2 to 4 mg/kg/day divided every 6 to 8 hours
Maximum: 200 mg/day IV
Oral:
Treatment: 4 to 8 mg/kg twice daily, every 12 hours
Maximum: 300 mg/day orally
Maintenance: 2 to 4 mg/kg/day orally once daily
Maximum: 150 mg/day orally
9 Gastric Ulcer
1 month to 16 years:
IV: 2 to 4 mg/kg/day divided every 6 to 8 hours
Maximum: 200 mg/day IV.
Oral:
Treatment: 4 to 8 mg/kg twice daily, every 12 hours
Maximum: 300 mg/day orally
Maintenance: 2 to 4 mg/kg/day orally once daily
Maximum: 150 mg/day orally
10 Gastroesophageal Reflux Disease

Neonatal:
IV: 1.5 mg/kg IV as a loading dose followed 12 hours later with 1.5 to 2 mg/kg/day IV divided every 12 hours. Alternatively, a continuous IV infusion may be administered at a rate of 0.04 to 0.08 mg/kg/hour (1 to 2 mg/kg/day) after a loading dose of 1.5 mg/kg has been given.

Continuous IV infusion: Loading dose: 1.5 mg/kg/dose, followed by 0.04 to 0.08 mg/kg/hour infusion (or 1 to 2 mg/kg/day).
Oral: 2 mg/kg/day divided into 2 doses, administered every 12 hours.

1 month to 16 years:
IV: 2 to 4 mg/kg/day divided every 6 to 8 hours
Maximum: 200 mg/day. Alternatively, an initial IV bolus dose of 1 mg/kg given once, followed by a constant IV infusion at a rate of 0.08 to 0.17 mg/kg/hour (2 to 4 mg/kg/day) may be administered.
Oral: 4 to 10 mg/kg/day administered in 2 divided doses, every 12 hours.
Maximum: 300 mg orally day
11 Erosive Esophagitis
1 month to 16 years:
IV: 2 to 4 mg/kg/day divided every 6 to 8 hours
Maximum: 200 mg/day. Alternatively, an initial IV bolus dose of 1 mg/kg given once, followed by a constant IV infusion at a rate of 0.08 to 0.17 mg/kg/hour (2 to 4 mg/kg/day) may be administered.

Oral: 4 to 10 mg/kg/day administered in 2 divided doses, every 12 hours.
Maximum: 300 mg orally day
12 Dyspepsia
Children greater than or equal to 12 years:
75 mg orally once 30 to 60 minutes before eating food or drinking beverages which cause heartburn.
Maximum: 150 mg/24 hours
Duration of therapy: Do not use for more than 14 days.

It is pertinent from the above various dosage regimen that it is useful to prepare once a day Ranitidine dosage form delivering 75 mg, 150 mg and 300 mg dose over 24 hours.
The effective treatment of erosive esophagitis requires administration of 150 mg of ranitidine 4 times a day. A conventional dose of 150 mg can inhibit gastric acid secretion up to 5 h but not up to 10 h. An alternative dose of 300 mg leads to plasma fluctuations; thus an extended release dosage form of ranitidine hydrochloride is desirable (Somade and Singh, 2002). The short biological half-life of drug (~2.5-3 h) also favors development of an extended release formulation.
Ranitidine is absorbed only in the initial part of the small intestine and has 50% absolute bioavailability (Lauritsen et al., 1990; Grant et al., 1989) due to pre-systemic hepatic metabolism. Moreover, colonic metabolism of ranitidine is partly responsible for the poor bioavailability of ranitidine from the colon (Basit and Lacey, 2001). These properties of ranitidine hydrochloride do not favour the traditional approach to extended release delivery.
The t1/2 of emptying of small intestine varies from 6 – 8.5 hrs. It is desirable that significant amount of dose is released in this time for actives such as Ranitidine having major absorption in small intestine.
The product monograph on Zantac reports as follows:
There is a significant linear correlation between the dose administered and the inhibitory effect upon gastric acid secretion for oral doses up to 300 mg. A plasma ranitidine concentration of 50 ng/mL has an inhibitory effect upon stimulated gastric acid secretion of approximately 50%. Estimates of the IC50 range from 36 to 94 ng/mL. Following the administration of 150 mg ranitidine orally, plasma concentrations in excess of this lasted for more than 8 hours and after 12 hours, the plasma concentrations were sufficiently high to have a significant inhibitory effect upon gastric secretion. In patients with duodenal ulcer, 150 mg oral ranitidine every 12 hours significantly reduced mean 24-hour hydrogen ion activity by 69% and nocturnal gastric acid output by 90%.
Furthermore, 300 mg oral ranitidine at night is as effective in reducing 24-hour
intragastric acidity as 150 mg ranitidine given orally twice daily.
Therefore, it can be concluded as follows:
a. a dose higher than 300 mg is not needed
b. for an inhibitory effect of Ranitidine, plasma ranitidine concentration of 50 ng/ml (IC50 range from 36 to 94 ng/mL) is sufficient
c. Even 150 mg dose provides after release up to 8 – 12 hrs sufficient plasma concentration to achieve IC50.
Hence it is desirable to have a dosage form which releases Ranitidine in unique manner to maintain plasma concentration above IC50 all the time.
For example, if after administration of 300 mg dose, if around half the dose is released in first 8 hrs, it will be sufficient to keep levels of Ranitidine above IC50 over next 8 hrs i.e. 8-16 hrs. Hence, it is desirable to prepare a dosage form which releases half of the Ranitidine in 8 hrs in pulsatile manner where one can target maximum absorption window. Such dosage form is likely to keep the plasma Ranitidine concentration above IC50 for next 8 hrs i.e. 16 hrs from the administration. At the end of 12 – 16 hrs, when plasma concentration is depleting, release of another small dose will help to keep plasma levels above IC50 and third dose releasing from 16 hrs to 24 hrs will once again inhibit depletion of plasma concentration of Ranitidine over next 8 hrs which would overlap with first 4 hrs of the next day.
Preparing any dosage form of Ranitidine hydrochloride to control its release poses several challenges. First, it is a highly water soluble drug and to make it release in an extended manner is a challenge. Second, since most widely used dosage of this highly water soluble drug are 150 and 300 mg, a high concentration of release controlling agent is essential to control release of such high doses. Third, if total of Ranitidine hydrochloride and one or more release controlling agents amount to more than 80 %, preferably more than 90 % of total formulation, the processing to final dosage form is difficult. For example, when the dosage form is a tablet, achieving good hardness and / or friability within the specified limits become difficult. Even if both hardness and friability values are satisfactory, dissolution does not meet the specified release pattern and hence such dosage form is not desirable.
Friability poses one of the major issues for compositions having high amounts of total of Ranitidine hydrochloride and one or more release controlling agents. For example, tablets prepared should be good enough to withstand pressure during handling, packaging, transportation and on shelf.
The present invention addresses all of the above problems by providing a floating pulsatile drug delivery system comprising a composition comprising three components wherein such composition exhibits desired release pattern over 24 hrs without any hardness and / or friability related issues.
Thus, in a first aspect, the present invention provides a floating pulsatile drug delivery system comprising a pulsatile and an extended release composition of H2 receptor antagonists particularly Ranitidine. The dose of H2 receptor antagonists particularly Ranitidine is divided in two parts such that the some part exhibits a pulsed release or pulsatile release and the remaining part exhibits an extended release. Both the parts together provide release of H2 receptor antagonists particularly Ranitidine over 24 hours. Within dosage form, the active is divided into two parts in a ratio of from 5:1 to 1:5 and more preferably from 4:1 to 1:4. And most preferably from 3:1 to 1:3. The dose division would depend upon pharmacokinetics of active ingredient or H2 receptor antagonist. For Ranitidine ratio is more preferably from 3:1 to 1:3 and most preferably from 2.5:1 to 1:2.5. In a preferred embodiment, ratio of Ranitidine in pulsatile form to Ranitidine in an extended form is from around 1:1.25 to 1:1.75. In another embodiment, ratio of Ranitidine in pulsatile form to Ranitidine in an extended form is from around 1:2 to 1:3. In yet another embodiment, ratio of Ranitidine in pulsatile form to Ranitidine in an extended form is from 1.5:1. In yet another embodiment, ratio of Ranitidine in pulsatile form to Ranitidine in an extended form is from 2.5:1.
It is not necessary that only Ranitidine in pulsatile section is released in pulsatile manner and Ranitidine in extended section is released in an extended manner. Therefore, an overlap is possible such that some Ranitidine in pulsatile section may be released in an extended manner and some Ranitidine in an extended portion is released in 6-8 hrs. However major pulsatile release is contributed by the Ranitidine in pulsatile section and major extended release is contributed by the Ranitidine in extended section. By modifying ratio of Ranitidine in pulsatile and extended sections, up to 60 % release of Ranitidine in first 8 hrs can be achieved.
Pulsatile or pulsatile release section is formed by that portion of Ranitidine formulation which contains less than 20 % of release controlling agent. It has two parts, an inner dosage form / inner phase / inner tablet containing low or no amounts of release controlling agent and outer coating part having less than 20 %, preferably less than 15 % of release controlling agent.
Extended release section is formed by that portion of Ranitidine formulation which contains more than 20 %, preferably more than 25 % of release controlling agent of the total weight of coated composition.
In this aspect, pulsatile section may contain from around 50 – 250 mg of Ranitidine and extended portion may contain from around 250 – 50 mg of Ranitidine.
As, 300 mg of Ranitidine corresponds to 336 mg of Ranitdine HCl, such amount shall be taken into account take while considering preparing dosage forms of Ranitidine.
In an embodiment, pulsatile section contains 100 mg of Ranitidine and extended release section contains 236 mg of Ranitidine. In yet another embodiment pulsatile portion contains 136 mg of Ranitidine and extended portion contains 200 mg of Ranitidine. In yet another embodiment, pulsatile portion contains 200 mg of Ranitidine and extended portion contains 136 mg of Ranitidine. One more embodiment has 168 mg of Ranitidine in each of the pulsatile portion and an extended portion.
In a second aspect, the present invention provides coated inlay tablet composition of Ranitidine or tablet in tablet composition of Ranitidine. Both the external and internal phases of the inlay tablet contains Ranitidine. The inlay tablet is coated with a coating containing at least one excipient that modifies or controls release of Ranitidine i.e. release controlling agent. The external phase contains at least one release controlling agent and preferably two or more release controlling agents. Internal phase is an immediate release composition containing no or low amounts of release controlling agent. Low amounts of release controlling agent is up to 20 %, preferably less than 10 % and most preferably less than 5 % of total weight of coated tablet. High amounts of release controlling agent is at least 20 %, preferably at least 25 % of the total weight of the coated tablet. Coating has one or more release controlling agents.
In an inlay tablet according to the present invention, inner phase (inside tablet) and outer coating together form pulsatile section and external phase (outside tablet) forms extended section.
In an embodiment, inlay tablet comprises
1. an internal phase having 10 – 20 % of Ranitidine of total weight of coated tablet and no release controlling agent,
2. external phase having 20 – 30 % of Ranitidine and at least 20 % and preferably at least 20 % of one or more release controlling agents of total weight of coated tablet,
3. coating comprising having less than 20 % of release controlling agent of total weight of coated tablet.
In an embodiment, inlay tablet comprises
1. an internal phase having around 12 – 16 % of Ranitidine of total weight of coated tablet and no release controlling agent,
2. external phase having 23 – 28 % of Ranitidine and at least 20 % and preferably at least 25 % of one or more release controlling agents of total weight of coated tablet,
3. coating comprising having less than 15 % of release controlling agent of total weight of coated tablet.
It is understood by the person skilled in the art that the dosage of different drugs are different. Even in the category of H2 receptor antagonists, the doses of famotidine such as 20 mg and 40 mg are significantly lower than doses of Ranitidine such as 150 mg and 300 mg. However it is understood that the division of doses in internal or external phases would fall in the ratio of 5:1 to 1:5. Based on solubility of the active and its dose, a person skilled in the art would be able to employ the best division of doses in each of the sections / phases. Also based on solubility and desired release pattern, a person skilled in the art would employ higher or lower concentration or single or multiple release controlling agents.
Inlay tablet of Ranitidine according to a preferred embodiment has combination of release controlling agents which together make up around 40 % of the total weight of the coated tablet. Out of around 40 %, 30 % release controlling agents are present in an external phase and around 10 % of release controlling agents are present in a coat.
In a third aspect, the present invention covers a composition of Ranitidine having following in vitro release pattern in dissolution medium
not more than 10 % in 4 hrs, preferably not more than 10 % in 6 hrs,
not more than 60 % in 8 hrs, preferably not more than 50 % in up to 8 hrs, and
not more than 90 % in 12 hrs , preferably not more than 80 % in 12 hrs, most preferably, not more than 80 % in 16 hrs. The dissolution conditions are as follows,
Water – 900ml, Apparatus- Paddle with sinker, RPM- 100, Temp- 37°C, Time points- 4, 6, 8, 12, 16 and 24 hours, Detector- UV 314 nm.
Release of first portion is less than 10 % in about 4 – 6 hrs. Thus at the end of any hour from 4 hrs to 6 hrs, less than 10 % of Ranitidine is released. In one embodiment, release at the at end of 4 hrs is 8 % but at the end of 6 hrs is 15 %. In another embodiment, release at the end of 6 hrs is 7 %. It is important that not more than 10 % is released at the end of 4 hrs and preferably at the end of 6 hrs. The cumulative release at the end of 8 hrs is not more than 60 % and preferably not more than 50 %. Thus, at the end of 8 hrs, less than 60 % and preferably less than 50 % of Ranitidine is released. Not more than than 90 % of Ranitidine is released in 12 hrs, preferably not more than 80 % is released in 12 hrs, most preferably not more than 80 % is released in 16 hrs. In one embodiment, around 20 – 25 % of Ranitidine is released over last 12 hrs. In another embodiment around 10 – 15 % Ranitidine is released over last 12 hrs. The desired release in last 12 hours can be achieved by choosing i) desired release controlling agents or their combinations and ii) employing required amounts of one or more release controlling agents.
The biological half-life of Ranitidine is 2 – 3 hrs, hence, it is essential that some substantial amount of Ranitidine is released over last 8 hours so that it is further available for 2-3 hrs after release.
In an embodiment, up to 30 % of Ranitidine is released over last 8 – 12 hrs. In another embodiment, around 27 – 29 % of Ranitidine is released over last 8 – 12 hrs.
The specific in vitro release pattern is important to enable this unique pulsatile and extended release dosage form of Ranitidine to serve as once a day dosage form. The overall pattern of release is as follows:
Sr. No. Hours % Release
1 First 4 hrs 0 - 10 %
2 First 8 hrs Not more than 60 %
3 First 12 hrs Not more than 90 %, preferably not more than 80 %.

wherein dissolution medium is water at 100 RPM paddles and with sinkers.
To achieve the above in vitro release profile, at least one, preferably at least two and most preferably at least three release controlling agents are used. In an embodiment having three release controlling agents, one is used in coating and the other two are used in external phase. In one more embodiment, at least four release controlling agents are used. Out of the four, one is used in coating and the other three are used in external phase. In yet another embodiment, at least five release controlling agents are used. Out of the five, two are used in coating and the other three are used in external phase.
According to any one or more aspects of the present invention, preferably combination of release controlling agents are used to control release of Ranitidine which is a highly soluble drug. The combination employs hydrophilic components such as hydrophilic polymers, hydrophilic gums or hydrophilic polysaccharides and hydrophobic polymers. The hydrophilic polymers are water soluble or water swellable polymers and hydrophobic polymers are water insoluble polymers. Additionally pH sensitive polymers can be incorporated.
In a preferred embodiment, hydrophilic polymers/ gums / polysaccharides are used in external phase of an inlay tablet whereas hydrophobic polymers are used alone or in combination with hydrophilic polymers in coating of a coated inlay tablets.
In yet another preferred embodiment, the pulsatile and an extended release inlay tablet according to the present invention contains at least two hydrophilic components in an external phase and no release controlling agent in the internal phase. The inlay tablet is coated by two coating, first immediately adjacent to core has hydrophobic polymer alone or combination of hydrophilic and hydrophobic polymer and the second coating has pH sensitive polymer.
In one more preferred embodiment, the pulsatile and an extended release inlay tablet according to the present invention contains at least two hydrophilic components in an external phase and no release controlling agent in the internal phase. The inlay tablet is coated by a single coating having both hydrophobic and pH sensitive polymers.
In yet another preferred embodiment, the pulsatile and an extended release inlay tablet according to the present invention contains three hydrophilic components in an external phase and no release controlling agent in the internal phase. The inlay tablet is coated by a single coating having both hydrophobic and hydrophilic polymers.
Hydrophilic polymers, gums and polysaccharides together comprises of following
sodium carboxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, propylene glycol alginate, sodium alginate, carboxymethyl cellulose, poly(vinylpyrrolidone)-(vinyl acetate) copolymer, polyvinyl alcohol, hydrophilic gums also include natural hydrophilic gums, heteropolysaccharides, xanthan gum, gellan gum, locust bean gum, gum karaya, guar gum, gum acacia, gum tragacanth, propylene glycol ester, homopolysaccharides, galactomannan, glucomannan, alkali metal carageenates, alginates, cellulose alkyl carboxylates, carboxymethyl cellulose, carboxyethyl cellulose, alkali metal salts of cellulose alkyl carboxylates, sodium carboxymethyl cellulose, carboxypolymethylene, hydroxypropyl methylcelluloses, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxyethyl methylcellulose, polyethylene glycols, polyethylene oxides, alginate salts, natural polysaccharides, gum arabica, carrageenan and crosslinked acrylic polymer such as Carbomer 934P and any combinations thereof.
The polysaccharides are selected from the group consisting of locust bean gum, xanthan gum, tragacanth, xylan, arabinogalactan, agar, gellan gum, scleroglucan, guar gum, apricot gum (Prunus armeniaca, L.), alginate, carrageenan, acacia gum, dragon gum, hog gum, talha, dextran, and gum Arabic and mixtures thereof.
Hydrophobic polymers include ethyl cellulose or aqueous polymeric dispersions containing acrylic methacrylic copolymers, cellulose acetate and other cellulose derivative polymers.
The pH sensitive polymers include esters of cellulose, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, polyvinyl acetate phthalate, pH-sensitive methacrylic acid/methylmethacrylate copolymers, shellac, and mixtures thereof.
In one embodiment, the pulsatile and an extended release inlay tablet according to the present invention contains
1. 12 – 16 % of ranitidine in an inner phase / inner tablet
2. 23 – 28 % of ranitidine in an external phase / outside tablet
3. 23 – 28 % of Xanthan gum in an external phase / outside tablet
4. 0.01 – 0.1 % of HPMC in an external phase / outside tablet
5. 0.01 – 0.1 % of carbomer in an external phase / outside tablet
6. 2 % - 10 % of hydroxy propyl methyl cellulose in coat of the tablet
wherein all % are expressed as w/w of coated tablet.
In a preferred embodiment, the pulsatile and an extended release inlay tablet according to the present invention contains
1. 12 – 16 % of ranitidine in an inner phase / inner tablet
2. 23 – 28 % of ranitidine in an external phase / outside tablet
3. 23 – 28 % of Xanthan gum in an external phase / outside tablet
4. 0.01 – 0.1 % of HPMC in an external phase / outside tablet
5. 0.01 – 0.1 % of carbomer in an external phase / outside tablet
6. 4% - 8% of ethyl cellulose in coat of the tablet
7. 0.5% - 3% of HPMC in coat of the tablet
In second embodiment, the pulsatile and an extended release inlay tablet according to the present invention contains
1. 12 – 16 % of ranitidine in an inner phase / inner tablet
2. 23 – 28 % of ranitidine in an external phase / outside tablet
3. 23 – 28 % of Alginic acid or salt in an external phase / outside tablet
4. 0.1 – 10 % of HPMC in an external phase / outside tablet
5. 0.1 – 10 % of carbomer in an external phase / outside tablet
6. 4 % - 8% of ethyl cellulose in coat of the tablet
7. 0.5% - 3% of HPMC in coat of the tablet

In one more embodiment, the pulsatile and an extended release inlay tablet according to the present invention comprises
1. 20 % of ranitidine in an inner phase / inner tablet
2. 20 % of ranitidine in an external phase / outside tablet
3. 1 - 5 % of carrageenan in an external phase / outside tablet
4. 1 – 10 % of locust bean gum in an external phase / outside tablet
5. 0.01 – 10 % of HPMC in an external phase / outside tablet
6. 1 – 20 % carbomer in an external phase / outside tablet
7. 2 - 10 % of 1 :1 of ethyl cellulose and hydroxypropylmethyl cellulose phthalate,
wherein all % are expressed as w/w of coated tablet.
In yet another embodiment, the pulsatile and an extended release inlay tablet according to the present invention comprises
1. 20 % of ranitidine in an inner phase / inner tablet
2. 20 % of ranitidine in an external phase / outside tablet
3. 1 - 5 % of carrageenan in an external phase / outside tablet
4. 1 – 10 % of locust bean gum in an external phase / outside tablet
5. 0.01-5 % of HPMC in an external phase / outside tablet
6. 1 – 20 % carbomer in an external phase / outside tablet
7. 10 - 20 % of 1 :1 of ethyl cellulose and hydroxypropylmethyl cellulose phthalate,
wherein all % are expressed as w/w of coated tablet.
In a preferred embodiment, internal phase has active, diluent, binder and disintegrant whereas external phase has active, diluent, binder and release controlling agent. In another embodiment, internal phase has active, diluent and disintegrant.
Diluents include organic materials such as carbohydrate and modified carbohydrates, such as for example, sugars, sugar alcohols and celluloses; inorganic materials such as calcium phosphates and others and co-processed diluents such as those containing starch and lactose, cellulose and lactose etc. and other conventional diluents.
Binders are selected from saccharides and their derivatives such as disaccharides for example, sucrose, lactose; and polysaccharides and their derivatives such as starches, cellulose or modified cellulose such as microcrystalline cellulose and cellulose ethers such as hydroxypropyl cellulose (hpc); sugar alcohols such as xylitol, sorbitol or maltitol; protein such as gelatin, and synthetic polymers such as polyvinylpyrrolidone (pvp), polyethylene glycol (peg) and any other conventional binder.
Disintegrants include Crosslinked polymers such as crosslinked polyvinylpyrrolidone (crospovidone), crosslinked sodium carboxymethyl cellulose (croscarmellose sodium), starches and the modified starch such as sodium starch glycolate and includes any superdisintegrant.
Glidants include fumed silica, talc, and magnesium carbonate and any conventional glidant.
Lubricants include common minerals like talc or silica, and fats, e.g. vegetable stearin, magnesium stearate, calcium stearate or stearic acid and any conventional lubricant.
Preferred coating agents are hydroxyl propyl methyl cellulose, ethyl cellulose and their combinations.
Preferred coating agents include hydroxyl propyl methyl cellulose phthalate, methacrylic acid / methylmethacrylate copolymers.

The present invention is further illustrated by reference to the following examples which does not limit the scope of the invention in any way.
Examples
Example 1
Sr.
No. Ingredients Unit Formula
(mg/Tab) 100000 Tablets
(Kg)
Dry Mix ( IR Part)
1 Ranitidine HCL 136 13.6
2 Microcrystalline cellulose 102 90 9
3 Croscarmellose sodium 30 3
Lubrication
4 Magnesium stearate 3 0.3
5 Arosil 200 2 0.2
ER Part Dr Mix
6 Ranitidine HCL eq. to Ranitidine 200 20
7 Xanthan Gum 214.29 21.43
8 Hydroxy Propyl Methyl Cellulose K15CR 21.79 2.179
9 Carbomer Homopolymer Type ‘C’
(Carbopol 980) 14 1.4
10 Povidone (PVP K-30) 19.82 1.982
Lubrication
11 Magnesium Stearate 3.75 0.375
12 Colloidal silicon dioxide 5.357143 0.536
Total weight of Uncoated Tablet 740 74
Barrier Membrane - DR
13 OPADRY® HPMC EC Coating ]* 110 11
14 Water QS QS
15 IPA QS QS
Total weight of coated Tablet 850 78
*containing 55-70% EC and 10-20% of HPMC
Process of preparing pulsatile ER formulation of Ranitidine according to the present invention has following steps
WEIGHING:
Ranitidine hydrochloride, microcrystalline cellulose, croscarmellose sodium, magnesium stearate, aerosil 200
SIFTING:
Ranitidine hydrochloride (40#), Microcrystalline cellulose (40#), Croscarmellose sodium (40#), Magnesium Stearate (60#), Aerosil 200 (40#),
DRY MIX:
Charge in the cage blender in the following order,
Ranitidine Hydrochloride IP, Microcrystalline cellulose NF, Croscarmellose sodium NF, Mix in cage blender for 30 min at around 17 RPM to form dry blend.
LUBRICATION:
Add above sifted Colloidal silicon dioxide IP & Magnesium Stearate IP to the bin containing blend in cage blender, close tightly and Mix for 5 minutes at around 17 RPM to form lubricated blend.
COMPRESSION:
Compress the lubricated granules using 8 mm Round shape plain punch. This is inner phase.

Manufacturing process of CR layer:
WEIGHING:
Ranitidine Hydrochloride IP, Xanthan Gum NF, Carbomer Homopolymer Type ‘C’(Carbopol 980) NF, Povidone (PVP K30) IP, HPMC K15CR USP, Colloidal silicon dioxide IP, Magnesium Stearate IP and Opadry Orange AMB 80W53259 IH.

SIFTING:
Ranitidine Hydrochloride IP (40#), Xanthan Gum NF (40#), Carbomer Homopolymer Type
‘C’(Carbopol 980) NF (40#), Povidone (PVP K30) IP (40#), HPMC K15CR USP (40#), Colloidal silicon dioxide IP (40#), Magnesium Stearate IP (40#) and Opadry Orange AMB 80W53259 IH
DRY MIX:
Charge in the cage blender in the following order,
Ranitidine Hydrochloride IP, Xanthan Gum NF Carbomer Homopolymer Type ‘C’ (Carbopol 980) NF , Povidone (PVP K30) IP & HPMC K15CR USP Mix in cage blender for 30 min at17 RPM to form dry blend

LUBRICATION:
Add above sifted Colloidal silicon dioxide IP 5.0 Kg & Magnesium Stearate IP 3.50 kg to the bin containing blend in cage blender, close tightly and Mix for 5 minutes at 17 RPM to form a lubricated blend.

COMPRESSION:
Compress the lubricated granules using 8 mm Round and 19X8.8 mm Oval shape plain punch using suitable inlay tablets compression machine.

COATING OF CORE TABLET FOR PULSATILE RELEASE
The coating material is procured containing ethyl cellulose from 55-70% EC and HPMC from 10-20% and containing plasticizer such as PEG and talc as other excipients. Alternatively 5 % w/w, combination of ethyl cellulose N10 (rupturable polymer) and hydroxypropyl methyl cellulose E15 (erodible polymer) was prepared in 90:10% w/w isopropyl alcohol: distilled water. The solution plasticized with plasticizer such as dibutyl phthalate 20% w/w and talc 5% w/w added as glidant. These percentages were based on dry polymer weight. The dispersion was stirred by using magnetic stirrer throughout the coating process. The prepared dispersion is sprayed on previously dried core tablet for 20 min in conventional pan until the desired percentage weight gain achieved. After coating, the tablets were dried in coating pan for 30 min at 50°C and then in hot air oven for 1 h at 45°C to remove residual solvent.

Example 2
Sr.
No. Ingredients Unit Formula
(mg/Tab) 100000 Tablets
(Kg)
Dry Mix ( IR Part)
1 Ranitidine HCL 100 10
2 Microcrystalline cellulose 102 90 9
3 Croscarmellose sodium 35 3.5
Lubrication
4 Magnesium stearate 3 0.3
5 Arosil 200 2 0.2
ER Part Dr Mix
6 Ranitidine HCL eq. to Ranitidine 236 21.8
7 Xanthan Gum 209.28 20.92
8 Hydroxy Propyl Methyl Cellulose K15CR 21.79 2.17
9 Carbomer Homopolymer Type ‘C’
(Carbopol 980) 14.00 1.4
10 Povidone (PVP K-30) 19.82 1.98
Lubrication
11 Magnesium Stearate 3.75 0.375
12 Colloidal silicon dioxide 5.357143 0.535
Total weight of Uncoated Tablet 740 74
Barrier Membrane - DR
13 OPADRY® HPMC EC Coating* 110 11
14 Water QS QS
15 IPA QS QS
Total weight of coated Tablet 850 78
*containing 55-70% EC and 10-20% of HPMC
Process is same as described in example 1.
Example 3
Sr.
No. Ingredients Unit Formula
(mg/Tab) 100000 Tablets
(Kg)
Dry Mix ( IR Part)
1 Ranitidine HCL 136 13.6
2 Microcrystalline cellulose 102 90 9
3 Croscarmellose sodium 30 3
Lubrication
4 Magnesium stearate 3 0.3
5 Arosil 200 2 0.2
ER Part Dr Mix
6 Ranitidine HCL eq. to Ranitidine 200 20
7 Xanthan Gum 214.29 21.43
8 Hydroxy Propyl Methyl Cellulose K15CR 21.79 2.179
9 Carbomer Homopolymer Type ‘C’
(Carbopol 980) 14 1.4
10 Povidone (PVP K-30) 19.82 1.982
Lubrication
11 Magnesium Stearate 3.75 0.375
12 Colloidal silicon dioxide 5.357143 0.536
Total weight of Uncoated Tablet 740 74
Barrier Membrane - DR
13 OPADRY® HPMC (K15 Premium Coating ]* 110 11
14 Water QS QS
15 IPA QS QS
Total weight of coated Tablet 850 78
* contains 50 – 70 % of HPMC
Process is same as described in example 1.
Example 4
Sr.
No. Ingredients Unit Formula
(mg/Tab) 100000 Tablets
(Kg)
Dry Mix ( IR Part)
1 Ranitidine HCL 100 10
2 Microcrystalline cellulose 102 90 9
3 Croscarmellose sodium 35 3.5
Lubrication
4 Magnesium stearate 3 0.3
5 Arosil 200 2 0.2
ER Part Dr Mix
6 Ranitidine HCL eq. to Ranitidine 236 21.8
7 Xanthan Gum 209.28 20.92
8 Hydroxy Propyl Methyl Cellulose K15CR 21.79 2.17
9 Carbomer Homopolymer Type ‘C’
(Carbopol 980) 14.00 1.4
10 Povidone (PVP K-30) 19.82 1.98
Lubrication
11 Magnesium Stearate 3.75 0.375
12 Colloidal silicon dioxide 5.357143 0.535
Total weight of Uncoated Tablet 740 74
Barrier Membrane - DR
13 OPADRY® HPMC (K15 Premium Coating ]* 110 11
14 Water QS QS
15 IPA QS QS
Total weight of coated Tablet 850 78
* contains 50 – 70 % of HPMC
Process is same as described in example 1.

References:
1. Product Monograph, Zantac for ranitidine tablets USP, 150 mg, 300 mg
ranitidine injection USP, 25 mg/mL by GlaxoSmithKline Inc.; Submission Control No: 179097, Date of Revision: January 15, 2015.
2. Lauritsen K. Clinical pharmacokinetics of drugs used in the treatment of gastrointestinal diseases. Clin. Pharmacokinet. 19: 11-31, 94-125(1990).
3. Grant S. Ranitidine: an updated review of its pharmacodynamics and pharmacokinetic properties and therapeutic use in peptic ulcer and other allied diseases. Drugs. 37:801-870(1989).
4. Basit A, Lacey L. Colonic metabolism of Ranitidine: implications for its delivery and absorption. Int. J. Pharm. 227(1-2):157-165, 2001