FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENTS RULES, 2003
Provisional Specification
(See section 10 and rule 13)
NOVEL ORAL DELIVERY OF DESMOPRESSIN AND ITS SALTS
PANACEA BIOTEC LIMITED
A company incorporated under the laws of India having their office at 104, SAMARPAN COMPLEX, NEW-LINK ROAD, CHAKALA, ANDHERI (E), MUMBAI 400099,
MAHARASHTRA, INDIA
The following specification describes the invention

NOVEL ORAL DELIVERY OF DESMOPRESSIN AND ITS SALTS
This invention relates to novel pharmaceutical formulations of desmopressin or a pharmaceutically acceptable salt thereof, to methods of their preparation and to their use in the treatment and prophylaxis of diseases in mammals, particularly humans.
Particularly, this invention relates to a pharmaceutical oral dosage form of desmopressin or a pharmaceutically acceptable salt thereof, wherein upon administration to a patient, the dosage form releases desmopressin in a timed pulsatile release manner.
More specifically, the present invention relates to a pharmaceutical formulation as an oral dosage form comprising desmopressin, or a pharmaceutically acceptable salt thereof, as a therapeutic active ingredient, together with a pharmaceutically acceptable excipient, diluent or carrier, or mixture thereof, wherein the dosage form releases a first effective amount of a desmopressin compound, followed by a time interval or intervals during which substantially no desmopressin compound is released, and after which time interval or intervals, further amount or amounts of desmopressin compound is released from the dosage form.
The pharmaceutical formulation described herein is preferably a once-a-day oral dosage form of desmopressin. This once-a-day oral dosage form, preferably administered in the evening, is such that the first effective amount of desmopressin is released immediately on administration to a patient, while the further amount or amounts of desmopressin may be released, after a time lag, at a predetermined time, either all at once or over a period of time as sustained amounts.
This once-a-day oral dosage form of desmopressin is stable and effective at a reduced dosage amount; it may have a reduced dosing frequency, would be more bioavailable and may have reduced side effect profile.
BACKGROUND OF THE INVENTION
Desmopressin (l-desamino-8-D-arginine vasopressin, dDAVP), a nonapeptide, is an analogue of the hormone vasopressin. Desmopressin has decreased vasopressor activity and increased antidiuretic activity compared to vasopressin. This pharmacological profile enables Desmopressin to be clinically used for antidiuresis without causing significant increases in blood pressure.
Desmopressin is commercially available as the acetate salt in injection form, tablet form and as a nasal spray, and is commonly prescribed as an antidiuretic in the treatment of conditions like diabetes insipidus, nocturnal eneuresis and urinary incontinence. An oral tablet dosage form of Desmopressin is approved for the treatment of central diabetes insipidus and primary nocturnal enuresis.
The currently marketed desmopressin tablets are conventional immediate release dosage forms, which need to be given twice or three times daily to achieve the required level of antidiuresis.
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They often cause adverse effects related to water intoxication and hyponatremiaa, like headache, nausea/vomiting and bloating. Also, the dose of the tablets is quite high (0.1 - 0.2 mg) compared to the intranasal or intravenous doses, since oral bioavailability of desmopressin is only 0.16%.
Thus there is a need for improvement in the currently available oral formulations of desmopressin, especially with regards to improved bioavailability, reduced side effects and frequency of administration.
Drugs like desmopressin, which have short half-lives, and hence need to be given multiple times daily, are good candidates for modified drug delivery systems. However, desmopressin is susceptible to development of patient tolerance, if administered in a continuous, prolonged manner. Also, desmopressin, a polypeptide is found to be stable only in a narrow pH range of about 4-6. Considering these factors, no satisfactory modified release formulations of desmopressin have been reported in the literature.
Hence, an attempt has been made in the present invention to overcome these drawbacks and provide for a new, better and improved therapy of desmopressin. The invention described herein, which comprises a pulsatile release system, and which can be given once daily, benefits from the washout period between the 'pulses', and thus decreases the chances of developing drug tolerance. More particularly, the formulation described in the invention shows enhanced bioavailability and hence a reduction in the dose required to produce the desired therapeutic effects. Still more particularly, the invention would exhibit fewer side effects, which are related chiefly to water intoxication and hyponatremia, and hence may improve patient compliance.
For nocturnal enuresis, preferably, a single dose having an effective amount of desmopressin is administered to a person before sleep. However in some instances, a second dose has to be administered during the daytime for continued effect. This second dose often leads to side effects, like bloating, fluid retention and headache. The dosage form described in the invention exhibits effective but lower plasma levels throughout the day, when fluid intake is higher, and has higher plasma levels at night, when effectiveness is required. Thus, the invention provides for a superior overall management of antidiuretic therapy.
The plasma profile associated with the administration of a drug compound may be described as a "pulsatile profile" in which pulses of high active ingredient concentration, interspersed with low concentration or nil concentration troughs, are observed. A pulsatile profile containing two peaks may be described as "bimodal", a pulsatile profile containing more than two peaks may be described as "multimodal". Similarly, a composition or a dosage form that produces such a profile upon administration may be said to exhibit "pulsed release" of the active ingredient.
United States Patent No. 5,047,398 assigned to Ferring B.V, claims an antidiuretic composition for humans, of desmopressin and pharmaceutical^ acceptable carrier, in a solid oral dosage form for absorption in the gastrointestinal tract of said humans. It describes a conventional immediate release tablet composition of desmopressin, which needs to be given multiple times daily. The desmopressin dissolves and is absorbed in the gastrointestinal tract of a human.
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United States Patent No 5,763,405 assigned to Ferring B.V, claims an oral pharmaceutical composition comprising desmopressin, an enteric coat soluble at and above pH 5.5, selected from polymers having dissociable carboxyl groups, and a buffering agent buffering at a pH of from 2 to 6. Thus it relates to stabilized compositions of desmopressin, which comprise of active ingredient and buffer formed into particles, and the particles contained in the tablets or capsules are enteric coated for delayed release of its contents in the upper part of the small intestine. These compositions do not provide a timed pulsatile release formulation of the active ingredient as described in the present invention.
United States Patent No. 5,788,987 provides a method for treating early morning pathologies, using a time-specific controlled release formulation, administered prior to sleep and which delivers the active agent at the time of awakening. Thus the invention relates to a delayed release formulation, where the whole of the dose is released at the more appropriate time (e.g. at about the time of awakening). The '987 invention particularly relates to methods for treating conditions or pathologies, the symptoms of which are more pronounced in the early morning.
PCT Application No.WO2005046646 relates to blister packs for solid dosage forms of desmopressin or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable adjuvant, wherein the solid dosage form is adapted to prevent moisture related degradation of said desmopressin. The application also relates to solid dosage forms of desmopressin or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable adjuvant, wherein the solid dosage form comprises an agent that provides a pH in the range of from 4.5 to 5.5; with the proviso that said solid dosage form does not comprise fish gelatin or an enteric coating. The WO'646 invention also does not relate to a times pulsatile release formulation of desmopressin as described in the present invention.
None of the above-described formulations of desmopressin provide a pulsed release of the drug such that there can be a reduction in the dosage amount, dosing frequency as well as reduction in side effects.
There are many references in the prior art describing formulations that provide a pulsatile release of the drug. United States Patent No. 5,413,777 to Sheth et al., relates to a pulsatile once-a-day delivery system for the administration of minocycline, the antibacterial, for the prolonged controlled release of the drug over a period of 24 hrs. United States Patent No. 5,260,068 to Chen et. al, is directed to a multiparticulate pulsatile drug delivery system and it claims a specific unit dosage form for administering a therapeutic agent which is very different from the present invention as described herein. United States Patent No. 6,555,136 relates to pulsatile delivery of methyl phenidate and an additional drug using a swelling agent, an osmotic agent and a film-forming polymer. United States Patent Application 20050095294 describes modified release pharmaceutical compositions of modafinil, where drug-containing cores are coated with enteric and other polymers to optimize the drug delivery at predetermined time intervals.
None of the above-described prior arts have mentioned desmopressin as the active ingredient with the several advantages as put forth in the present invention.
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To the best of our knowledge, the pharmaceutical oral dosage forms for desmopressin and/or its pharmaceutically acceptable salts as described in our invention are previously unknown and completely unsuggested by the art.
SUMMARY OF THE INVENTION
Accordingly, it is a primary object of the present invention to address the shortcomings in desmopressin therapy by providing a novel pharmaceutical formulation of Desmopressin.
The invention provides for an oral dosage form comprising desmopressin or a pharmaceutically acceptable salt thereof, method for their preparation and their use in the treatment of disorders like Diabetes Insipidus, nocturnal enuresis and urinary incontinence.
Particularly, the invention provides an oral dosage form, wherein desmopressin is released in a timed pulsatile release manner.
More particularly, the invention provides an oral dosage form comprising at least two individual drug-containing units, each of which having a similar or different drug release profile. The invention further comprises two or more individual drug-containing units, each of which release the drug at a predetermined time interval either all at once or over a period of time.
Also, the invention provides a stable desmopressin formulation, which exhibits improved bioavailability, reduced dosage, a lesser frequency of administration and reduced side effects.
It is an object of the present invention to provide an oral dosage form of desmopressin such that the dosage units are either enclosed in a capsule as drug containing particles or beads or pellets or granules or minitablets or are compressed into tablets which may be single, bilayered, trilayered or multilayered, or are particles or beads or pellets or granules compression coated as inlay tablets.
It is a further object of the invention to provide an oral dosage form of desmopressin having a release mechanism that differs from that of the release mechanism of DDAVP® (desmopressin oral tablet), and provides a pharmaceutical formulation that is effective to treat Diabetes insipidus, nocturnal enuresis and urinary incontinence, as well as other conditions that are treatable by desmopressin.
DETAILED DESCRIPTION OF THE INVENTION
It is an objective of the present invention to provide an improved oral formulation of desmopressin, which can be administered once a day and releases desmopressin in a time controlled pulsed manner and which shows improved bioavailability, such that it is effective at a lower dose and produces less side effects.
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As disclosed herein and as used in the composition and methods of the present invention, a desmopressin compound includes desmopressin or any of its pharmaceutically acceptable salt, like desmopressin acetate.
The invention provides for a decreased dose of desmopressin, in the range of about 20u.g to about 200(u.g per tablet, preferably from about 20ug to about 100 ug, and more preferably from about 20ju.g to less than l00ug per tablet.
In accordance with the present invention, the desmopressin is provided in a pulsatile release dosage form, described in more details below.
Pulsatile release dosage form:
Pulsatile delivery indicates a plurality of drug doses released at spaced time intervals. Generally, upon ingestion of the dosage form, release of the first dose is substantially immediate i.e. within 1-2 hrs. of ingestion. This initial pulse is followed by a first time interval during which there is 'substantially no release' of the drug, after which a second dose is released, typically 3-5 hrs later. This second dose is released either immediately ie. within 1 to 2 hours or over a period of time of about 5 to 6 hours. In certain embodiments, release of the second dose may be followed with a second interval of 'substantially no release', which is again followed by a "pulse" of drug release. In a preferred embodiment here, either two or three release pulses are provided. However, the invention also includes dosage forms that provide more than three pulses.
For the purpose of the present invention, the term 'substantially no release' is defined as a mean release of about 10% of the drug from the composition, which ranges from about 0% to about 20% release of the drug from the composition.
As defined in the present invention, the dosage unit from which the drug is released immediately is the IR component of the dosage form and the dosage unit from which the drug is released over a period of time, is the SR component of the dosage form.
In an embodiment of the invention, a pulsatile release form of desmopressin includes an amount of desmopressin suitable for immediate release, in combination with a second amount of desmopressin, formulated such that the second amount is released completely as a 'pulse' after a lag time period during which substantially no drug is released, i.e. 'two IR pulses'.
In another embodiment, the above dosage form includes a third pulse of desmopressin, which is released after a second suitable non-release interval, i.e. 'three IR pulses'.
In a yet another embodiment, the dosage form of the present invention includes an amount of desmopressin suitable for immediate release in combination with a second amount of desmopressin formulated such that the second amount is released immediately after the first amount and its release is extended over a period of time, i.e. an TR+SR pulse'.
In a more preferred embodiment, the present invention includes an amount of desmopressin suitable for immediate release in combination with a second amount of desmopressin formulated
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such that the second amount has a delay before onset and its release is extended over a period of time, i.e. an 'IR+SR pulse'.
In an alternative embodiment, the pharmaceutical formulation of the invention may be in the form of a liquid dosage form, wherein desmopressin or its pharmaceutically acceptable salt, is dissolved and/ or dispersed, either alone or in combination with excipients, in a pharmaceutically acceptable vehicle, to form the IR pulse; and the second amount of desmopressin or its pharmaceutically acceptable salt, is also dispersed in the vehicle in the form of granules, particles, beads or pellets, to form the second pulse.
In the above embodiment, the second pulse may be formulated to release the entire drug amount immediately as a pulse or the second amount may be released over a period of time as a sustained release amount of desmopressin. Also, in the above embodiment, the second pulse may be released either immediately after the first pulse or it may be released after an interval of "substantially no release" period as defined above. The above embodiment, alternatively, may also exhibit more than two pulses of drug release.
Each type of pulsed system can be formulated in a various ways. Typically, the profiles can be achieved with dosage forms comprising of multiple-unit-containing tablets or capsules.
In an embodiment, each dosage unit comprises a drug-containing particle or bead ('bead' refers to drug coated inert supports) or pellet or granules. A first group of these granules, beads or pellets releases drug almost immediately upon ingestion, and second and optionally third groups release after specific time gaps.
Accordingly, these multiple granules, beads or pellets are filled into capsules or compressed into a tablet, using suitable excipients. Alternatively, the granules, beads or pellets can be formulated into an inlay tablet. Still alternatively, one group of units, preferably the IR component units, are formulated as beads or pellets or granules and the remaining group of units are formulated as coated or uncoated tablets.
In another embodiment, each dosage unit comprises a compressed or molded tablet, wherein each of the tablets within the capsule provides a different drug release profile.
In a still other embodiment, a multiple layer tablet is formulated, such that each layer shows a different drug release profile.
A most preferred embodiment consists of the immediate release fraction formulated as granules or pellets or beads and the delayed sustained fraction formulated as coated tablets, and filled into capsules or formulated into inlay tablets.
As appreciated by those skilled in the art, a number of methods are available for preparing delayed and sustained release drug fractions. The delayed release units in the present capsules or tablets can be prepared, for example, by coating the drug composition with select rate controlling polymeric membrane coating materials, but not including enteric coating polymers.
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Examples of rate controlling polymeric membranes include swellable hydrophilic and insoluble hydrophobic polymers like
cellulose ethers such as methylcellulose (MC), ethylcellulose (EC), hydroxyethylcellulose (HEC), hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), hydroxypropyl ethylcellulose (HPEC), carboxymethyl cellulose (CMC), crosslinked carboxymethyl cellulose (croscarmellose) and its alkali salts, ethylhydroxyethylcellulose (EHEC), hydroxyethyl methylcellulose (HEMC), hydrophobically modified hydroxyethyl cellulose (HMHEC), hydrophobically modified ethylhydroxyethylcellulose (HMEHEC), carboxymethyl hydroxyethylcellulose (CMHEC), carboxymethyl hydrophobically modified hydroxyethyl cellulose (CMHMHEC), and the like;
cellulose esters like cellulose acetates with different degrees of esterification, and the like;
vinyl pyrrolidone polymers such as crosslinked polyvinylpyrrolidone or crospovidone, copolymers of vinyl pyrrolidone and vinyl acetate;
alkylene oxide homopolymers such as polypropylene oxide, preferably ethylene oxide homopolymers
an acrylic acid polymer such as cross-linked polymer available under the trade name Carbopol®. or homopolymers and co-polymers of acrylate or methacrylate monomers for example polymethacrylates marketed under the brand names of Eudragit.® particularly Eudragit.® RS and Eudragit.® RL.
In certain embodiments the preferred rate controlling membrane is Cellulose acetate, commercially available as Cellulose acetate CA 320S and Cellulose acetate CA398 10. These are non-enteric cellulose esters, which do not show pH-dependant solubility characteristics. Their films are essentially insoluble yet semi permeable. Sustained release through the films can be achieved by incorporation of water-soluble materials in the films to increase the ability of the drug to diffuse through it.
The cellulose acetate polymer may be present in an amount ranging from about 1.0% to about 80% of the formulation, preferably about 5% to about 60% and more preferably from about 10% to about 40%>.
Alternatively, the polymeric coating layer may be comprised of other substances that are capable of becoming freely permeable following hydration in aqueous fluids. Such substances include polysaccharides, such as gelatin, saccharose, sorbitol, mannose, and jaluronic acid; polyaminoacids; polyalcohols; polyglycols; and the like. In addition to the foregoing, the polymeric coating layer may also include additional excipients such as lubricants, flow promoting agents, plasticizers, antisticking agents, natural and synthetic flavorings and natural and synthetic colorants.
Alternatively, the delayed and sustained fractions can also be formulated as matrix-type systems using the same polymers as described above.
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For preparing formulations containing two or more IR pulses, optionally disintegrating agents can be added in the dosage units. The disintegration-enhancing agent accelerates the disintegration of the core once the rate controlling polymeric membrane coating layer is removed by dissolution or swelling or erosion and hence allows the complete drug amount in the pulse to be released at one time.
It is understood that desmopressin dosage forms described herein may be orally administered with an inert diluent or carrier. In addition to the active ingredient, it may additionally contain any of the following: binders, diluents, buffers, penetration enhancers, disintegrants, lubricants, glidants, surfactants, preservatives, colorants, stabilizers, vehicles, flavorants, sweeteners, viscosity modifiers and the like.
Desmopressin, a polypeptide, is highly susceptible to degradation in the intestinal tract, via proteolysis, by various enzymes, and the degradation is accelerated in the extreme pH ranges. Experimentally, highest stability of the drug has been found to be at a pH range of about 4-6. When the IR component (ie. The pulse which is released substantially immediately upon administration) of the dosage form is released in the stomach, the buffers (or alkalisers) provide desmopressin with a microenvironment in the 4 - 6 pH range and thus protect it from degradation in the acidic contents of the stomach. Buffers used in the invention include, but are not limited to, sodium bicarbonate, sodium borate, sodium carbonate, triethanolamine, sodium citrate dihydrate, meglumine, L-lysine, L-histidine, protamine. The IR component of the pharmaceutical formulation of the invention includes the buffering agent in a range of about 2.0% to about 90% of the core weight, preferably about 10% to about 80% of the core weight and more preferably about 20%o to about 60% of the core weight. The buffering agent may be included in the IR component either by mixing with the drug to form a matrix-type system, or may be layered on to the IR component to form a coating. Alternatively, the buffer component may be supplied separately comprising an element of a 'kit'.
The epithelial cells lining the luminal side of the GIT are a major barrier to drug delivery following oral administration. Most orally administered drugs are absorbed by passive transport. Drugs, which are lipophilic, permeate the epithelium by the transcellular route whereas drugs that are hydrophilic are restricted to the paracellular route. Paracellular pathways occupy less than 0.1%> of the total surface area of the intestinal epithelium. Further, tight junctions, which form a continuous belt around the apical part of the cells, restrict permeation between the cells by creating a seal between adjacent cells. Thus, oral absorption of hydrophilic drugs such as peptides can be severely restricted. Other barriers to absorption of drugs may include hydrolyzing enzymes in the lumen brush border or in the intestinal epithelial cells, the existence of the aqueous boundary layer on the surface of the epithelial membrane which may provide an additional diffusion barrier, the mucus layer associated with the aqueous boundary layer and the acid microclimate which creates a proton gradient across the apical membrane. Absorption, and ultimately bioavailability, of a peptide drug is thus, highly reduced.
One of the strategies for delivering drugs across the GIT cell layers is the use of permeation enhancers. They increase the absorption of peptides by numerous mechanisms, like, dissolving the barrier mucus layer, reversible interaction with GI epithelial cells, transient opening of
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paracellular junctions etc. Numerous permeation enhancers are known in the literature. Permeation enhancers used in the invention include, but are not limited to 23-lauryl ether, Aprotinin, Azone, Benzalkonium chloride, Cetylpyridinium chloride, Cetyltrimethylammonium bromide, Dextran sulfate, Laurie acid, Lysophosphatidylcholine, Menthol, Methoxysalicylate, Methyloleate, Oleic acid, Phosphatidylcholine, Polysorbate 80, Sodium EDTA, Sodium glycocholate, Sodium glycodeoxycholate, Sodium lauryl sulfate, Sodium salicylate, Sodium taurocholate, and Sodium taurodeoxycholate. Alternatively, certain other known bioavailability enhancers like P-Glycoprotein inhibitors (PGP inhibitors) may also be included to improve the bioavailability of drug in the dosage form of the present invention.
Additional examples of additives that may be considered in practicing the present invention are found in the "Handbook of Pharmaceutical Excipients" Ed. A.H. Kibbe, 3rd edition, American Pharmaceutical Association, USA and Pharmaceutical Press, UK, 2000.
The methods of preparing the pharmaceutical formulations of the present invention include techniques commonly disclosed in the literature and well known to a person skilled in the art. One embodiment of the present invention comprises mixing an effective quantity of desmopressin with suitable excipients to form the IR component, making granules or beads or pellets of the other component or components, by methods well known in the art, and coating them with rate controlling polymers to delay their release for a specific period of time. The components are then filled into a suitable capsule.
Another embodiment of the present invention comprises mixing an effective quantity of desmopressin with suitable excipients to form the IR component in the form of granules, pellets or beads, compressing the remaining component or components into tablets and coating the tablets with rate controlling polymers to delay their release for a specific period of time. The components are then filled into a suitable capsule.
Yet another embodiment of the present invention comprises mixing an effective quantity of desmopressin with suitable excipients to form the IR component as granules, pellets or beads, and formulating the other component to delay and then sustain its release over a period of time. This can be achieved by using rate-controlling polymers to coat the component or to make a 'matrix' type system. The processes for achieving this are well known to a person skilled in the art. The delayed sustained release component can be in the form of granules, pellets beads or tablets, and along with the IR component, filled into a capsule.
In an alternative embodiment, all the various components of the pulsatile system are compressed as separate layers of a multi-layer tablet, each layer exhibiting a different release profile.
In a still another embodiment, the granules, pellets or beads of all components are compressed together with suitable excipients to form a single layer tablet.
In yet another embodiment, an inlay tablet is formed, using special compression equipments.
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In an alternative embodiment, the novel pharmaceutical formulation is supplied in the form of a kit, which comprises of drug component(s) and a buffer component. Each of the component(s) may be in the form of granules, tablets, pellets or beads.
In a yet alternative embodiment, the invention is formulated as a liquid dosage form, by dissolving and/ or dispersing the various components of the system to form a pulsatile release suspension.
The following examples given do not limit the scope of the invention and are presented merely as illustrations of the invention.
EXAMPLE 1
The following is an embodiment of our invention:

IR component:
No. Ingredient Unit Qty(mg)
1 Desmopressin acetate 0.02
2 Lactose 42.98
3 Meglumine 50.0
4 Hydroxypropyl methyl cellulose (HPMCE15) 5.0
5 Magnesium stearate 1.5
6 Polyethylene glycol 400 0.5
7 Purified water Qs.
SR component:
No. Ingredient Unit Qty (mg)
Core tablet
8 Desmopressin acetate 0.02
9 Lactose monohydrate 42.98
10 Lecithin 0.3
11 Magnesium stearate 1.0

Coat composition
12 Cellulose Acetate CA 320S 53.25
13 Cellulose Acetate CA 398 10 8.01
14 Hydroxypropyl methyl cellulose (HPMCE15) 5.72
15 Polyethylene glycol PEG 8000 7.25
1. Blend desmopressin acetate and lactose uniformly and coat the blend with a solution of HPMC El 5. Dry the above and blend with meglumine and magnesium stearate.
2. Separately blend desmopressin acetate and lactose, granulate with an aqueous solution of lecithin, dry the granules and blend with magnesium stearate.
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3. Compress the blend of step 2 into tablets of suitable size.
4. Coat the tablets using coating solution of Cellulose Acetate, Hydroxypropyl methyl cellulose and Polyethylene glycol to a suitable weight gain.
5. Dry the tablets.
6. Fill the blend of step 1 and tablets of step 5 into hard gelatin capsules.
EXAMPLE 2

IR component:
No. Ingredient Unit Qty (mg)
1 Desmopressin acetate 0.02
2 Lactose 90.98
3 Sodium carbonate 200.0
4 Hydroxypropyl methyl cellulose (HPMCE15) 5.0
5 Magnesium stearate 4.0
6 Polyethylene glycol 400 0.5
7 Purified water Qs.
SR component:
No. Ingredient Unit Qty (mg)
Core tablet
8 Desmopressin acetate 0.03
9 Lactose monohydrate 97.67
10 Vitamin E-TPGS 0.3
11 Magnesium stearate 2.0

Coat composition
12 Cellulose Acetate CA 398 10 48.26
13 Hydroxypropyl methyl cellulose (HPMCE15) 5.72
14 Polyethylene glycol PEG 3350 7.25
The procedure followed is the same as example 1, except the final step involves preparation of compression coated tablet.
EXAMPLE 3

IR component:
No. Ingredient Unit Qty (mg)
1 Desmopressin acetate 0.05
2 Lactose 89.95
3 Sodium bicarbonate 500.0
4 EudragitElOO 5.0
5 Magnesium stearate 5.0
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1. Coat desmopressin acetate on lactose and divide equally into two parts.
2. Coat one part of step 1 with Eudragit El00 and dry at 40° to 45°C. Blend the dried powder with sodium bicarbonate and magnesium stearate.
SR component:
No. Ingredient Unit Qty (mg)
Core tablet
6 Second part of Desmopressin acetate coated on lactose Equivalent to 0.025mg Desmopressin acetate
7 Lactose monohydrate 99.525
8 Gelucire 44/14 0.3
9 Purified water qs
10 Magnesium stearate 1.0

Coat composition
11 Cellulose Acetate CA 320S 53.25
12 Hydroxypropyl methyl cellulose (HPMCE15) 5.72
13 Polyethylene glycol PEG 3350 7.25
3. Granulate lactose with Gelucire 44/14 and blend with second part of active of step 1. Mix with magnesium stearate.
4. Compress into tablets and coat with a solution of Cellulose Acetate, Hydroxypropyl methyl cellulose and Polyethylene glycol to a suitable weight gain.
5. Dry the tablets.
6. Fill the blend of step 2 and tablets of step 5 into hard gelatin capsules.
EXAMPLE 4
IR component:
No. Ingredient Unit Qty (mg)
1 Desmopressin acetate 0.03
2 Lactose monohydrate 92.97
3 L-lysine 100.0
4 Polyvinyl pyrrolidone PVP K-30 6.0
5 Purified water qs
6 Magnesium stearate 1.0

No. Ingredient Unit Qty (mg)
Core tablet
7 Desmopressin acetate 0.02
8 Lactose monohydrate 92.68
9 Poloxamer F-68 0.3
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10 Polyvinyl pyrrolidone PVP K-30 6.0
11 Magnesium stearate 1.0

Coat composition
12 Cellulose Acetate CA 320S 53.25
13 Cellulose Acetate CA 398 10 8.01
14 Hydroxypropyl methyl cellulose; (HPMCE15) 5.72
15 Polyethylene glycol PEG 8000 7.25
In this embodiment, wet granulation is carried out in the manufacturing of granules for IR and SR components. IR granules are formulated as a blend ready for filling and SR granules are compressed to form tablets and coated with the Cellulose Acetate coating solution. The final dosage form is obtained by filling the IR component part along with SR tablet into empty hard gelatin capsule shell using a suitable capsule filling equipment.
EXAMPLE 5
IR component
No. Ingredient Unit Qty (mg)
1 Desmopressin acetate 0.06
2 Lactose monohydrate 93.83
3 Sodium glycine carbonate 250.0
4 Polyvinyl pyrrolidone PVP K-30 6.0
5 Purified water qs
6 Magnesium stearate 1.0
SR COMPONENT:
No. Ingredient Unit Qty (mg)
Core tablet
7 Desmopressin acetate 0.02
8 Lactose monohydrate 93.50
9 Polaxamer F-68 0.3
10 PVP K-30 6.0
11 Magnesium stearate 1.0

Coat composition
12 Eudragit RL/RS 50.0
13 Hydroxypropyl methyl cellulose; (HPMCE15) 5.72
14 Polyethylene glycol PEG 6000 7.25
The procedure followed is the same as example 4, except the coated tablet is placed in the IR tablet as compression coated formulation.
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EXAMPLE 6

IR component:
No. Ingredient Unit Qty(mg)
1 Desmopressin acetate 0.02
2 Dibasic calcium phosphate 94.83
3 Meglumine 100.0
4 Hydroxypropyl methyl cellulose (HPMC E5LVP) 5.0
5 Magnesium stearate 1.0
6 Polyethylene glycol 400 0.5
7 Purified water Qs.
SR component:
No. Ingredient Unit Qty (mg)
Core tablet
8 Desmopressin acetate 0.02
9 Dibasic calcium phosphate 99.53
10 Polysorbate 80 0.3
11 Magnesium stearate 0.15
100 mg
Coat composition
12 Ethyl Cellulose l0cps 40.0
13 Hydroxypropyl methyl cellulose (HPMC El5) 5.72
14 Polyethylene glycol PEG 8000 7.25
The procedure followed is the same as example 1. EXAMPLE 7

IR component:
No. Ingredient Unit Qty (mg)
1 Desmopressin acetate 0.02
2 Dibasic calcium phosphate 93.83
3 Di sodium citrate 200.0
4 Polyvinyl pyrrolidone PVP K-30 6.0
5 Purified water qs
6 Magnesium stearate 2.5
SR component:
No. Ingredient Unit Qty (mg)
Core tablet
7 Desmopressin acetate 0.02
8 Dibasic calcium phosphate 93.53
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9 Vitamin ETPGS 0.3
10 PVP K-30 6.0
11 Magnesium stearate 0.15

Coat composition
12 Cellulose Acetate CA 320S 53.25
13 Cellulose Acetate CA 398 10 8.01
14 Hydroxypropyl methyl cellulose; (HPMCE15) 5.72
15 Polyethylene glycol PEG 8000 7.25
The procedure followed is the same as example 4. EXAMPLE 8:

IR component:
No. Ingredient Unit Qty (mg)
1 Desmopressin acetate 0.02
2 Dibasic calcium phosphate 93.83
3 Disodium citrate 100.0
4 Polyvinyl pyrrolidone PVP K-30 6.0
5 Magnesium stearate 0.15
6 Purified water qs
SR component:
No. Ingredient Unit Qty (mg)
Core tablet
7 Desmopressin acetate 0.05
8 Dibasic calcium phosphate 93.50
9 Polysorbate 80 0.3
10 PVP K-30 6.0
11 Magnesium stearate 0.15

Coat composition
12 Cellulose Acetate CA 320S 53.25
13 Cellulose Acetate CA 398 10 8.01
14 Hydroxypropyl methyl cellulose; (HPMC El5) 5.72
15 Polyethylene glycol PEG 8000 7.25
The procedure followed is the same as example 4.
16

EXAMPLE 9:

IR component:
No. Ingredient Unit Qty (mg)
1 Desmopressin acetate 0.02
2 Lactose monohydrate 20.0
3 Meglumine 50.0
4 Magnesium stearate 1.0
SR component:
No. Ingredient Unit Qty (mg)
Core tablet
5 Desmopressin acetate 0.02
6 Lactose monohydrate 42.98
7 Lecithin 0.3
8 Magnesium stearate 1.0

9 Coat composition
10 Cellulose Acetate CA 320S 53.25
11 Cellulose Acetate CA 398 10 8.01
12 Hydroxypropyl methyl cellulose (HPMCE15) 5.72
13 Polyethylene glycol PEG 8000 7.25
1. Blend desmopressin acetate and lactose uniformly and further blend with meglumine and magnesium stearate.
2. Separately blend desmopressin acetate and lactose, granulate with an aqueous solution of lecithin, dry the granules and blend with magnesium stearate.
3. Compress the blend of step 2 into tablets of suitable size.
4. Coat the tablets using coating solution of Cellulose Acetate, Hydroxypropyl methyl cellulose and Polyethylene glycol to a suitable weight gain.

5. Dry the tablets.
6. 10 Fill the blend of step 1 and tablets of step 5 into hard gelatin capsules.
Dated 23rd day of January 2006



17

Vivek Kathpalia
NISHITH DESAI ASSOCIATES