FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule13)

1. TITLE OF THE INVENTION:
DEVICE FOR PROGRAMMED DELIVERY OF BIOLOGICAL MATERIAL
2. APPLICANT (S)
(a) NAME: WOCKHARDT LTD.
(b) NATIONALITY: INDIAN
(c) ADDRESS: D-4, M.I.D.C. Area, Chikaltharta, Aurangabad - 431210
( M.S) India
3. PREAMBLE TO THE DESCRIPTION
The present invention provides a device for the programmed delivery of biological material across the biological tissue. The device comprises two reservoirs one of which delivers the biological material immediately and the other reservoir delivers the biological material over a specified time. Separate drive mechanisms deliver the biological material in programmed fashion.
The following specification particularly describes the invention and the manner in which it is to be performed.

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4. Description
The present invention provides a device for the programmed delivery of biological material across the biological tissue. The device comprises two reservoirs one of which delivers the biological material immediately and the other reservoir delivers the biological material over a specified time. Separate drive mechanisms deliver the biological material in programmed fashion.
Dosed biological material delivery devices, often referred to as "injection pen device" are commonly used for routine injection of biologic materials. Injection pen device are normally used to deliver the basal doses of biological material. Further prior art devices for basal and bolus delivery of biological materials are available wherein
(i) they deliver precisely either the basal doses of biological material or bolus doses of biological material but not both by the drive mechanism simultaneously. Predominantly the drive mechanisms used are either a gas source or a combination of gas source and a mechanically stored energy or a purely mechanically stored energy. In situations where purely mechanical energy is being used, either a basal delivery of biological material or bolus delivery of biological material is achieved, but not both of them.
(ii) the devices which employ only mechanical energy as a sole mechanism of
delivery, it delivers only bolus or basal delivery of biological material but not
both, (iii) the devices which employ transfer of mechanical energy to hydraulic energy
and back to mechanical energy achieves both bolus delivery of biological
material and basal delivery of biological material.
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US Patent No 6,702,779 discloses a wearable, self-contained drug infusion device is disclosed that is capable of achieving the precise flow rate control needed for dose-critical drugs such as insulin.
US Patent No 6,939,324 discloses fluid delivery and measurement systems and methods.
US Application No 20050119618 discloses a hydraulic pump device and its use thereof, especially in a fluid delivery system.
PCT Application No WO07115039 discloses relates generally to fluid delivery devices and particularly to fluid delivery devices capable of delivering one or more medicaments to a patient to provide a sustained, basal delivery and/or a bolus delivery of each medicament.
The present inventors while working for suitable devices for programmed delivery of biological materials have found that there is a need
(i) For a mechanism which make use of only one source of energy i.e.
mechanical energy and minimum number of components and yet perform the
task, (ii) For more than one reservoir wherein same or different biological materials
are stored in separate reservoirs.
The term "Programmed Delivery" of biological material as used herein refers to delivery of biological material in a dual phase manner. Further the "Dual Phase " as used herein refers to such a delivery wherein one phase delivers biological material immediately and the other phase delivers the biological material in a specified time.
Dual phase delivery may be used interchangeably for bolus and basal delivery of biological material.
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Programmed delivery" may be tailored to delivery ot immediate delivery (bolus) ot biological material followed by delivery of biological material over a specified time (basal) further followed by delivery of immediate delivery (bolus) of biological material and the like as and when need arises.
One of the aspects of present invention provides for a fluid delivery device for programmed delivery of biological materials across biological barrier wherein the device comprises
(a) at least two reservoirs
(b) a drive mechanism
(c) a means for actuating drive mechanism
(d) at least one needle or microneedle
As used herein, the term " biological material " refers to an agent which possesses therapeutic, prophylactic, or diagnostic properties in vivo, for example when administered to an animal, including mammals, such as humans. The biological material is selected from the group comprising of peptides, proteins, carbohydrates, nucleic acid molecules, lipids and other pharmaceutically active ingredients or combinations thereof.
The pharmaceutically active ingredients may be one or more of anesthetics, analgesics, anti bacterials, anti virals, antiadrenergics, antiamebics, antianginals, antiarrhythmics, antibiotics, anticoagulants, anticonvulsants, antidepressants, antidiabetics, antidiuretics, antidyskinetics, antiemetics, antifungals, antihistaminics, antihyperparathyroids, antihypertensives, antiinflammatories, antimigraines, antineoplastics, antineoplastics, antiprotozoals, antipsychotics, antispasmodics, antithrombotics, antiulceratives, anxiolytics, astringents, bone resorption inhibitors, bronchodilators, cardiotonics, cholinergics, diaprostic agents, diuretics, hormones, steriods, hydrochloride as anineoplastic, hypnotics, immunomodulators, immunosuppresants, mucolytics, muscle relaxants, neuromuscular blocking agents, oxytocics, vasodilator and the like.
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The pharmaceutically active ingredients may further include one or more ketamine, chloroprocaine hydrochloride, alfentanil, amikacin, abacavir, bretylium tosylate, metronidazole, diltiazem hydrochloride, ciprofloxacin, dextran sulfate sodium, fosphenytoin sodium, rubidium chloride, insulin, desmopressin acetate, haloperidol lactate, dimenhydrinate, abelcet, diphenhydramine hydrochloride, paricalcitol, diltiazem hydrochloride, ketorolac, dihydroergoatmine mesylate, mitoxantrone hydrochloride, leuprolide acetate, metronidazole, aripiprazole, dicyclomine hydrochloride, dipyridamole, cimetidine hydrochloride, diazepam, zinc chloride, zoledronic acid, aminophyllin, digoxin, pyridostigmine bromide, diatrizoate sodium, furosemide, estrogen, androgen and the like, steriods such as glucocorticoid and the like, mechlorethamine hydrochloride, etomidate, mitoxantrone hydrochloride, tacrolimus, acetylcysteine, baclofen, vecuronium bromide, oxytocin nitroglyceine and the like.
The term "microneedle" refers to a device for transdermal or Intradermal delivery or removal of fluids without many of the risks associated with standard syringes. Microfabricated microneedle arrays are designed to pierce the stratum corneum skin barrier layer in a minimally invasive and pain-free manner to provide transient pathways for the delivery of macromolecules to the underlying skin epidermis. Since the needles are short, they do not reach the nerve-rich regions of the lower parts of the skin. As a consequence, the stimulus caused by microneedle insertion into the skin is weak and cause less pain. Such devices use arrays of small diameter needles that each deliver relatively small flow rates of fluid across or into a biological barrier, which together with the fluid delivered by other needles in the array, provide a clinically useful alternative to standard syringes.
The geometrical shape of microneedles can be selected from the group comprising of cylindrical, pyramidal, frustoconical and frustopyramidal.
The microneedles can be formed with shafts that have a circular cross-section in the perpendicular, or the cross-section can be non-circular. For example, the cross-section of
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the micro needle can be polygonal (e.g. star-shaped, square, triangular, pyramidal), oblong, or another shape such as frusto conical and frusto pyramidal. The shaft can have one or more bores.
The cross-sectional dimensions typically are between about 1 µm and 500 µm, and preferably between 10 and 100 µm. The outer diameter is typically between about 10 µm and about 100 µm, and the inner diameter is typically between about 3 µm and about 80 µm.
The length of the microneedles typically is between about 10 urn and 1 mm, preferably between 100 µm and 500 µm, and more preferably between 150 µm and 350 µm. The length is selected for the particular application, accounting for both an inserted and un inserted portion. An array of microneedles can include a mixture of microneedles having, for example, various lengths, outer diameters, inner diameters, cross-sectional shapes, and spacing between the microneedles. In transdermal applications, the "insertion depth" of the microneedles is preferably less than about 500 µm, so that insertion of the microneedles into the skin does not penetrate into the dermis, thereby avoiding contacting nerves which may cause pain. In such applications, the actual length of the microneedles typically is longer, since the portion of the microneedles distal the tip may not be inserted into the skin; the uninserted length depends on the particular device design and configuration. The actual (overall) height or length of microneedles should be equal to the insertion depth plus the un inserted length.
Suitable materials for manufacturing microneedles include one or more metals, ceramics, semiconductors or polymers which may be biodegradable or non biodegradable.
Standard size needles can be of any size ranging from 22 gauge to 36 gauge or more.
The metals can be selected from the group comprising of pharmaceutical grade stainless steel, gold, titanium, nickel, iron, tin, chromium, copper, palladium, platinum, alloys, silicon, silicon dioxide, and combinations thereof.
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Suitable non-biodegradable polymers include one or more cellulose, polycarbonate, polyester, or polyacrylamides. Suitable biodegradable polymers which include polymers of hydroxy acids such as lactic acid and glycolic acid polylactide, polyglycolide, polylactide-co-glycolide, and copolymers with PEG, poly anhydrides, poly (ortho)esters, polyurethanes, poly(butyric acid), poly (valeric acid), and poly (lactide-co-caprolactone).
In another embodiment of the invention, wherein fluid delivery device comprises two reservoirs, wherein one resenoir delivers biological material immediately and the other reservoir delivers biological material over a specified time.
In another embodiment of the invention, biological material to be delivered through the two reservoirs may be same or different.
In another embodiment of the invention, the reservoirs and the delivery reservoir are
made of either metal or non biodegradable polymeric material.

The metals can be selected from the group comprising of pharmaceutical grade stainless steel, gold, titanium, nickel, iron, tin, chromium, copper, palladium, platinum, alloys, silicon, silicon dioxide, and combinations thereof. Suitable non-biodegradable polymers include one or more cellulose, polycarbonate, polyester, or polyacrylamides.
In another embodiment of the invention, there is one drive mechanism corresponding to each reservoir and each drive mechanism comprises a piston, hollow piston rod, drive shaft, a spring and a ratchet and pawl.
Piston, hollow piston rod , drive shaft, and a ratchet and pawl mechanisms are made of either metal or non biodegradable polymer.
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In another embodiment of the invention, the drive shaft is located in hollow piston rod and there is an integral movement of auxiliary piston and piston wherein the auxiliary piston rod is attached to drive shaft.
In another embodiment of the invention, the ratchet and pawl facilitates prevention of piston moving back from its new position to earlier position on delivery of the biologic material.
In another embodiment of the invention, there is a separate known actuating mechanism for each of the drive mechanisms.
In another embodiment of the invention, the needle is of any available conventional standard size or the microneedles.
In another embodiment, a method of administering a biologically active material in a programmed manner from a fluid delivery device wherein one or both the reservoirs deliver the biological material by means of actuating means employing mechanical energy.
Mechanism for programmed delivery of biological material is as shown in Figure 1. The device comprises two reservoirs namely reservoir 1 & reservoir 2. In the Figure 1, the biological material in reservoir 1 caters to immediate delivery and the biological material in reservoir 2 caters to over a specified time. However, the biological material in reservoirs 1 and reservoir 2 may be the same or different. Adequate strength reservoir material will be chosen to withstand the tension of the spring during delivery period of the biological material which may extend from 24 hours to 48 hours or more as the case may be.
Reservoir 1 & reservoir 2 are each provided with a hollow piston rod (3) and piston (16). The biological material delivery is triggered by a mechanical mechanism (9 or 10). The
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two mechanical mechanisms each correspond to delivery of corresponding biological material from each of the reservoirs.
The details of mechanical mechanism is shown at "A".
The mechanical mechanism (9) comprises a hollow piston rod (3) which has internal thread (13) at its proximal end. A piston is attached at its distal end (16). A solid drive shaft (15) with external thread (14) at its distal end is located inside the hollow piston rod (3) and the external thread mates with the internal thread (13) of the hollow piston rod. One end of the extension rod (18) is connected to drive shaft (15) and the other end is connected to auxiliary piston rod (17). A spring (18) whose one end is biased against the rim (19) of the drive shaft (15) and the other end is biased against the housing cover (23). Spring (18) strength is appropriately determined depending on whether the biological material is of immediate delivery or over a specified time. It is normal that spring (18) is of lower strength for biological material of immediate delivery than that for over a specified time, both biological material being the same, considering the fact that higher quantity of immediate delivery of biological material delivered. The spring (18) strength determined to overcome the resistances of non return valves (5,6), fiictional losses of common distributor and pressure loss associated with delivery reservoir (7). The rate of a spring is the change in the force it exerts, divided by the change in deflection of the spring. For an extension or compression spring it has the units of lbf/in, N/mm, or similar. Spring properties chosen is such that it would expand equivalent to incremental delivery of constant throughput of either over a specified time or immediate delivery. Known actuating mechanism chosen is such that application of force (20) would result in piston movement corresponding to constant delivery of biological material over a specified time.
The mechanical mechanism (10) for the reservoir (2) will be the same as mentioned for the mechanical mechanism (9).
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Auxiliary piston rod (17), extension rod (18) and drive shaft (15) are molded as one unit or attached separately by other means. Hollow piston rod (3) and piston (16) are attached by threading means.
The mechanical mechanism shown at detail "A" is prevented from moving upwards by a ratchet (21) and pawl (22) mechanism whose details are shown at "B". The reservoirs (1,2), mechanical mechanism (9,10), timers (11,12), Non return valves (5,6), delivery reservoir (7) and microneedle (8) are housed in a housing (not shown).
Reservoir 1 and reservoir 2 can either have the same cross section piston or different cross section pistons depending on the variation biological material delivery of immediate nature or over a specified time. Larger the cross section of the piston higher is the delivery of biological material. Non return valves (5, 6) have been provided at the exit of the reservoir (1) and reservoir (2) as a safety measure to prevent the back entry of the biological material intended for the patient. The delivery of the biological material can be through microneedles (8) or conventional needle.
Timer (11) provided can be set to raise an alarm at a predetermined interval say 1 hour or 2 hour as per convenience. Timer can be mechanical, electromechanical or digital. When the alarm is raised the biological material is due for administration. Then the force (20) is applied on the actuating means shown at detail "A". The entire assembly of piston (16), hollow piston rod (3), drive shaft (15), auxiliary piston rod (17). which are held against spring bias moves down by a predetermined distance delivering the biological material through non return valve (5). Actuating mechanism for both the reservoirs are different. Actuating mechanism may be one in an another embodiment.
Another embodiment for programmed delivery of biological material is as shown in Figure 2. In this embodiment, there is no delivery reservoir like in Figure 1. Programmed delivery of biological material is achieved through an angled discharge pipe connected each of the reservoirs (1,2) through a common distributor (7). All other features, working mechanisms, components as mentioned with respect to Figure 1 are valid.
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While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
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We Claim:
1 A fluid delivery device for programmed delivery of biological materials across
biological barrier wherein the device comprises
(a) at least two reservoirs
(b) a drive mechanism
;{c) a means for actuating drive mechanism (d) at least one needle or microneedle
2 The fluid delivery device as in claim 1, comprises two reservoirs, wherein one reservoir delivers biological material immediately and the other reservoir delivers biological material over a specified time.
3 The fluid delivery device as in claim 1, biological material may be same or different.
4 The fluid delivery device as in claim 1, wherein the reservoirs and the delivery reservoir are made of either metal or non biodegradable polymeric material.
5 The fluid delivery device as in claim 1, wherein there is one drive mechanism corresponding to each reservoir and each drive mechanism comprises a piston, hollow piston rod, drive shaft, and a spring and a ratchet and pawl.
6 The fluid delivery device as in claim 5, wherein the drive shaft is located in hollow piston rod and there is an integral movement of auxiliary piston rod and piston wherein the auxiliary piston is attached to drive shaft.
7 The fluid delivery device as in claim 5, wherein the ratchet and pawl facilitates prevention of piston moving back from its new position to earlier position on delivery of the biologic material.
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8 The fluid delivery device as in claim 1, wherein means for actuating mechanism comprises a timer based on which the actuating mechanism triggered.
9 The fluid delivery device as in claim 1, wherein the needle is of any available conventional standard size or the microneedles.
10 A method of administering a biologically active material in a programmed manner from a fluid delivery device wherein two reservoirs deliver the biological material by means of an actuating means employing mechanical energy.
Dated this 05th day of June 2008 For Wockhardt Limited
(Mandar Kodgule) Authorized signatory
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