COMPLETE AFTER PROVISIONAL LEFT ON 22 / 5 / 06
FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENTS RULES, 2003
Complete Specification
[ See Sections 10 and rule 13 ]
Title: Modified Composition of Calcitriol
Applicant: (a) Astrone Research Limited
(b) Nationality: Indian
(c) 10l Floor, Premier House Bodakdev, Opp. Gurudwara Sarkhej - Gandhinagar Highway Ahmedabad 380054
The following specification particularly describes the invention and manner in which it is to be performed:

Field of Invention
The present invention relates to a modified composition of calcitriol. The pharmaceutical composition comprises of calcitriol, calcium salt and zinc and/or their substitutes, trace elements. Further this relates to the process for preparation of stabilized pharmaceutical compositions resulting therefrom.
Back Ground of the invention
Osteoporosis is a condition that features loss of the normal density of bone. Osteoporosis leads to abnormally porous bone that is more compressible like a sponge than dense like a brick. This disorder of the skeleton weakens the bone leading to an increase in the risk of breaking bones (bone fracture).
Normal bone is composed of protein collagen and calcium. Osteoporosis depletes both the calcium and the protein from the bone, resulting in either abnormal bone quality or decreased bone density. Bones that are affected by osteoporosis can fracture with only a minor fall or injury that normally would not cause a bone fracture. The fracture can be either in the form of cracking (as in a hip fracture) or collapsing (as in a compression fracture of the vertebrae of the spine). The spine, hips, and wrists are common areas of osteoporosis-related bone fractures, although fractures can also occur in other skeletal areas such as the ribs.
Calcium is the fifth most abundant element in the body. Calcium is an important structural component of bone and teeth and also is necessary for the normal function of all muscles (skeletal, heart, and smooth muscles) and nerves as well as the normal clotting of blood.
It is used for preventing and treating osteoporosis in individuals with low levels of calcium in their diets. It is also indicated in the prevention and treatment of vitamin D deficiencies, such as, osteomalacia and rickets (in children). As well, it is used in the management of hypocalcemia associated with hypoparathyroidism and renal
2

osteodystrophy, hyperparathyroidism secondary to renal failure, postmenopausal osteoporosis and in pregnancy for mother and foetus and implement during lactating period.
Calcitriol is essential for the absorption of calcium by body. Usual daily source is obtained from the ultraviolet rays of the sun and its action on our skin (90%) producing vitamin D3 and, from our diet (10%). With age, the process, which utilizes this, begins to be less efficient. Calcitriol is a vitamin D analogue. It works by increasing calcium absorption from the gut and decreasing calcium excretion, thereby producing a positive calcium balance.
Calcitriol must be protected from air and light. The drug substance exhibits good stability when stored at -15°C to -25°C In an argon atmosphere. Calcitriol is stable at room temperature when dissolved in a vegetable oil derivative, containing antioxidants, such as used in calcitriol soft gelatin capsules (Analytical Profiles of Drug Substances by Florey; ISBN 0-12-260808-9).
Calcitriol gets hydroxylated to form la, 24,25-trihydroxy cholecalciferol prior to intestinal absorption. Also Vitamin D and/or its derivative are required in absorption of Ca++ during pregnancy or for calcium supplement of post-menopausal women. Zinc helps in the growth of fetus and mother. Additionally Zinc is used as an antioxidant.
Trace amounts of some minerals are needed for the body to function properly. Taken as supplements, zinc can promote bone formation and help to prevent osteoporosis. Most people get enough trace elements in their diets. However, for the prevention and treatment of osteoporosis, supplements can be helpful. A zinc deficiency is associated with decreases in bone density. That is why it is important to maintain adequate levels of zinc in diet to prevent and/or treat osteoporosis.
3

WO02052954 discloses a nutritional composition for prevention or treatment of a bone condition, which comprises a source of protein, a source of carbohydrate, a source of fat, calcium, magnesium, zinc, vitamin D and vitamin K.
EP0834319 discloses A product for the management of osteoarthritic and rheumatoid arthritics pain in humans, comprising calcium with one or more of the nutritional elements, magnesium, zinc, vitamin D, copper and manganese, in the form of a tablet, capsule, liquid and injection.
Zinc is herewith added in the formulation as an elemental supplement, to have a proper growth of foetus and overall growth of the mother.
The present invention is a modified composition of calcitriol. The said composition comprises of calcitriol, calcium salt and zinc and/or their substitutes.
There are a number of pharmaceutical compositions, which suffer from instability problems due to the fact that the active component is susceptible, sensitive to certain types of degradation, thereby diminishing their attractiveness, effectiveness and, in some cases, rendering them unsuitable from a commercial standpoint.
Objects of Invention
First object of the present invention is to prepare the modified composition comprising calcitriol, calcium salt and zinc and/or their substitutes.
The further object is to develop the stable pharmaceutical formulation comprising calcitriol, calcium salt and zinc and/or their substitutes within a single dosage form.
The next object of the present invention is related to develop the pharmaceutical formulations for oral use.
4

Another object of the present invention is to prepare a fixed-dose-composition comprising pharmaceutical^ effective amounts of Calcium, Zinc and Calcitriol, or pharmaceutical^ acceptable salts or hydrates or both thereof.
Still another object of the present invention is to prepare a composition that can be used for the treatment of Calcium & Zinc deficiency.
Still another object of the invention is to prepare a palatable, orally administrable nutritional supplement like Zn, Calcium that can contain a relevant amount of one or more vitamins, a prenatally relevant amount of one or more minerals, or both. The invention includes calcium, zinc, calcitriol and mineral containing such as iron, cobalt and all other trace elements.
Still another object of the present invention is to prepare a single stabilized pharmaceutical composition comprises of calcitriol, calcium and Zinc and/or substitutes or salts or hydrates thereof in a single dosage form either tablet in tablet or layered tablet or conventional tablet
Summary of Invention
•\ The present invention relates to a modified composition comprising calcitriol, calcium salt and zinc and/or their substitutes. Further, this is a stable pharmaceutical formulation comprising calcitriol, calcium salt and zinc and/or their substitutes within a single dosage form for oral use. Further, the present invention relates to a process for preparation of the said composition that can be used for the treatment of calcium and zinc deficiency.
The dosage form of the present invention is a palatable, orally administrable nutritional supplement like zinc, calcium may also contain a relevant amount of one or more vitamins, precursor of vitamins, a prenatally relevant amount of one or more minerals, or both. The dosage form of the present invention is either conventional tablet, tablet in tablet or multilayered tablet.
5

Detailed Description of the invention
The present invention relates to a modified composition of calcitriol comprising of calcitriol, calcium salt and zinc and/or their substitutes.
The "dosage form" herein describes a formulation product of one or more active ingredients with one or more pharmaceutical excipients in the required proportions in such a way it becomes a stable product in terms of physical and chemical attributes and in vivo bioavailabilty as well; at the time of manufacturing and during its proposed shelf-life. This dosage form can be either tablet in tablet or a layered tablet.
The term "stability" used herein in relation to the composition according to the invention can be described as stability at least up to six months ait the intermediate storage conditions of 30° C and 65% relative humidity in the aluminum blister packs. This indicates a shelf life of 12 to 36 months at ambient conditions of temperature and relative humidity.
The new stabilized pharmaceutical composition of the present invention wherein the single dosage form comprises of compressed dosage form of calcitriol in compressed granules of calcium and zinc or salts or hydrates thereof, a tablet in tablet form (figure 1).
The present invention may also provide pharmaceutically stabilized composition wherein the single dosage form comprises of compressed dosage form of calcitriol and compressed dosage form of calcium and/or zinc or salts or hydrates thereof. In this form two/three compressed dosage forms remain separate from each other in a single dosage form.
6

The composition of the present invention comprises the ingredients as given below in the Table-1.
Table-1

Sr. No. Ingredients Range
1. Calcium Source 50-89%
2. Biologically active form of Vitamin D3 0.01-1%
3. Zinc Source 2-6%
4. Disintegrant 0-16%
5. Wetting Agent 0-5%
6. Binder 0-20%
7. Glidant 0-4%
8. Lubricant 0-4%
9. Anti-adherant 0-4%
10. Film forming polymer 0.25-10%
11. Plasticizer 0-4%
12. Opacifier 0.1-2%
13. Surface Smoother 0.1-1%
14. Solvent and stabilizer for Calcitriol 0.01-6%
15. Antioxidant 0.05 ppm- lOppm
16. Diluent 0-75%
17. Vehicle for film-coating solution Will not remain in the final product
18. Vehicle to prepare Calcitriol Solution Will not remain in the final product
Calcium source can be Calcium Carbonate, Calcium Citrate, Calcium Gluconate, Calcium Pidolate, Calcium Glucoheptonate, Calcium Lactate and the like.
The granulating agents or binders can be selected from the group comprising of Acacia, Glucose, Gelatin, Povidone, Starch, Sucrose, Tragacanth, Water and the like.
7

The lubricant can be selected from the group comprising of Fumaric Acid, Hydrogenated Vegetable Oil, Liquid Paraffin, Magnesium Lauryl Sulphate, PEG 4000 and 6000 (Macrogols), Sodium Benzoate, Sodium Lauryl Sulphate, Sodium Stearyl, Fumarate, Stearates; Calcium, Magnesium, Stearic Acid and the like.
The disintegrants can be selected from the group comprising of Alginic Acid, Sodium Alginate, Aluminium Magnesium Silicate, Carbon Dioxide, Croscarmellose Sodium, Cationic Exchange Resins, Crospovidone, Sodium Starch Glycollate, Starch and the like.
The glident in the present invention can be talc or the commonly used tablet glident.
The anti-adherant used in the present invention can be Colloidal Anhydrous Silica or commonly used tablet Anti-adherants.
The calcitriol or calcitriol source can be substituted by dihydrotachysterol, alphacalcidol and the like.
The zinc or zinc source can be substituted with Magnesium, Silicon, Vitamin C (Ascorbic Acid), Vitamin D, Manganese, Vitamin B6, Vitamin K and the like.
The tablet is film coated, wherein the film protects the core tablets from moisture and environmental conditions. The film also masks odour and taste. The film coat is mainly to protect calcitriol from photo degradation. The film coat also provides elegant appearance and patient compliance.
The process for preparation of the dosage form of the present invention is described along with but not limited to the examples.
The stabilized pharmaceutical compositions of the instant invention exhibit a number of advantages as follows:
8

1) The active component, e.g., calcitriol, is virtually preserved from any type of degradation by incorporation in fractionated triglycerides
2) They exhibit an extended shelf-life under normal storage conditions compared to conventional calcitriol formulations.
3) They exhibit minimal, if any, discoloration over a significant period of time.
4) They exhibit good stability as Calcitriol is stabilized in Medium Chain
Triglycerides with Antioxidants and is protected by outer tablet and film coating.
Such supplements are useful, for example, for administration to pregnant and lactating women, to women who anticipate becoming pregnant, and to humans in general for maintenance of a generally good state of health and nutrition.
To provide stabilized pharmaceutical compositions comprising Ca and zinc or pharmaceutically acceptable salts or hydrates thereof are in granules and Calcitriol is in dissolved form in stabilized fractionated triglycerides containing antioxidants.
The attainment of the above objects and advantages is made possible by the use of fractionated triglycerides (vegetable oil derivative) to formulate the preparation.
Comprises or comprising herein is taken to mean, "includes, among other things". It is not intended to be construed as "consists of only".
Description of figure
The bilayered and three layered tablets is simple two or three layer tablet
Figure - 1: This figure shows tablet in tablet form in bisect view. This comprises two tablets, wherein one inner tablet 1 is covered by the outer tablet 2.
9

Examples
The following examples further illustrate but by no means limit the present invention
Example 1:- Film Coated Tablet
Table - 2

Sr.No. Ingredients % WAV
1. Calcium Carbonate 85.15%
2. Sodium Starch Glycol late 1.36%
3. Sodium Lauryl Sulphate 1.70%
4. Maize Starch 3.75%
5. Purified Water Qs
6. Calcitriol Solution* 0.03%
7. Industrial Methylated Spirit Qs
8. Zinc Sulphate Monohydrate 3.78%
9. Maize Starch 0.82%
10. Purified Talc 0.82%
11. Magnesium Stearate 1.02%
12. Colloidal Anhydrous Silica 0.34%
13. Hydroxypropyl Methylcellulose E-50 0.46%
14. Ethyl Cellulose 0.11%
15. Propylene Glycol 0.29%
16. Titanium Dioxide 0.23%
17. Purified Talc 0.14%
18. Isopropyl Alcohol QS
19. Dichloromethane QS
Total 10 }%
10

*CALCITRIOL SOLUTION PREPARATION
Table-3

Sr.No. Ingredients Qty/Tablet (mg)
1. Calcitriol 0.25 μg
2. Medium Chain Triglycerides (Brand : Labrafac CC) 0.50
3. Butylated Hydroxy Anisole 0.10 μg
4. Butylated Hydroxy Toluene 0.05 μg
Total 0.500
1. Sift Calcium Carbonate, Sodium Starch Glycolate,Sodium Lauryl Sulphate through 40#. Mix well for few minutes
2. Keep Purified water for boiling. Disperse Maize starch in Purified water and prepared slurry. Prepare Starch Paste by adding Maize starch slurry in boiling water
3. Granulate step 1 with step 2.
4. Pass the wet mass through 10#
5. Keep the granules for drying.
6. Pass the dried granules through 16#.
7. Prepare Calcitriol solution along with Industrial Methylated spirit ( Calcitriol Solution: Calcitriol in Brand : Labrafac CC + Butylated Hydroxy Anisole + Butylated Hydroxy Toluene)
8. Adsorb the Calcitriol solution of step 7 on to the 20% granules of step 6. Air dry for few minutes and mix this granules with remaining 80% granules of step 6
9. Pass Zinc Sulphate, Maize Starch, Purified Talc, Magnesium stearate through 40#

10. Mix Step 8 and Step 9 well.
11. Carry out compression of the lubricated blend of step 10 using 18X8.5
11

mm Capsule shaped punches BL/PL.
12. Preparation of Film Coating solution:-
a) Disperse HPMC E-50 in Isopropyl Alcohol.
b) Disperse Ethyl Cellulose in Dichloromethane. Add Propylene Glycol to it.
c) Add step a to step b
d) Disperse Titanium Dioxide, Purified Talc to remaining Isopropyl Alcohol, and pass through colloid mill.
e) Add step d to step c. Mix properly.
f) Pass the solution through bolting cloth.
13. Carry out coating of compressed tablets of step 11 using coating solution
of step
Example :-2 Tablet in Tablet
Inner Tablet Composition
Table - 4

Sr.No. Ingredients % WAV
1. Calcium Carbonate 7.04%
2. Sodium Starch Glycollate 0.11%
3. Sodium Lauryl Sulphate 0.14%
4. Maize Starch 0.31%
5. Purified Water QS
6. Zinc Sulphate Monohydrate 0.31%
7. Maize Starch 0.07%
8. Purified Talc 0.07%
9. Magnesium Stearate 0.09%
10. Colloidal Anhydrous Silica 0.03%
11. Calcitriol Solution* 0.03%,
12

Outer Tablet Composition
Table - 5

Sr.No. Ingredients % WAV
1. Calcium Carbonate 78.11%
2. Sodium Starch Glycollate 1.25%
3. Sodium Lauryl Sulphate 1.56%
4. Maize Starch 3.44%
5. Purified Water QS
6. Zinc Sulphate Monohydrate 3.47%
7. Maize Starch 0.75%
8. Purified Talc 0.75%
9. Magnesium Stearate 0.93%
10. Colloidal Anhydrous Silica 0.31%
Coating composition
Table - 6
1. Industrial Methylated Spirit QS
2. Hydroxypropyl Methylcellulose E-50 0.46%
3. Ethyl Cellulose 0.11%
4. Propylene Glycol 0.29%
5. Titanium Dioxide 0.23%
6. Purified Talc 0.14%
7. Isopropyl Alcohol QS
8. Dichloromethane QS
Total 100%

1. Sift Calcium Carbonate, Sodium Starch Glycolate,Sodium Lauryl Sulphate through 40#. Mix well for few minutes.
2. Keep Purified water for boiling. Disperse Maize starch in Purified water and prepared slurry. Prepare Starch Paste by adding Maize starch slurry in boiling water
3. Granulate step 1 with step 2.
4. Pass the wet mass through 10#
5. Keep the granules for drying.
6. Pass the dried granules through 16#.
7. Prepare Calcitriol solution along with Industrial Methylated spirit ( Calcitriol Solution: Calcitriol in Brand : Labrafac CC + Butylated Hydroxy Anisole + Butylated Hydroxy Toluene)
8. Pass Zinc Sulphate, Maize Starch, Purified Talc, Magnesium stearate through 40#
9. Mix Step 6 to Step 8 well.

10. Keep aside 12 kg from the total blend.
11. Keep the remaining blend aside (133.50 kg)
12. Adsorb the Calcitriol solution of step 7 on the granules of step 10.
13. Air dry the resultant blend. (Blend 1)
14. Carry out compression of Blend 1 using 6.00 mm S.C PL/PL punches.
15. Carry out compression by placing tablet from above step into granules of the remaining blend of step 11 by using 18X8.5 mm oval shaped punches BL/PL.
14

Example :-3 Bilayered Tablet
Table-7

Sr.No. Ingredients %W/W
1. Calcium Carbonate 80.59%
2. Sodium Starch Glycollate 1.29%
3. Sodium Lauryl Sulphate 1.61%
4. Maize Starch 3.55%
5. Purified Water QS
6. Zinc Sulphate Monohydrate 3.58%
7. Maize Starch 0.77%
8. Purified Talc 0.77%
9. Magnesium Stearate 0.97%
10. Colloidal Anhydrous Silica 0.32%
11. Lactose (Spray dried) 6.45%
12. Calcitriol Solution* 0.03%
13. Industrial Methylated Spirit QS
14. Lake of Quinoline Yellow 0.03%
Total 100%
PART I:- CALCIUM CARBONATE AND ZINC GRANULES
1. Sift Calcium Carbonate, Sodium Starch Glycolate,Sodium Lauryl Sulphate through 40#. Mix well for few minutes
2. Keep Purified water for boiling. Disperse Maize starch in Purified water and prepared slurry. Prepare Starch Paste by adding Maize starch slurry in boiling water
3. Granulate step 1 with step 2.
4. Pass the wet mass through 10#
5. Keep the granules for drying.
6. Pass the dried granules through 16#.""
15

7. Pass Zinc Sulphate, Maize Starch, Purified Talc, Magnesium stearate through 40#
8. Mix step 6 to step 7.
PART II:- CALCITRIOL GRANULES
9. Prepare Calcitriol solution along with Industrial Methylated spirit(Calcitriol
Solution :Calcitriol in Brand : Labrafac CC + Butylated Hydroxy Anisole +
Butylated Hydroxy Toluene)
10. Adsorb the Calcitriol solution of Lactose (Spray dried) .Air dry.
11. Sift Lake of Quinoline Yellow through 100#. 12. Mix step ll to step l0.
13. Place part I granules and simultaneously part II granules & Carry out
compression achieve Bilayered tablet by 18X8.5 mm Oval shaped punches BL/PL.
16

Example :-4 Triple Layered Tablet
Table-8
Sr.No. Ingredients %W/W
1. Calcium Carbonate 73.74%
2. Sodium Starch Glycollate 1.17%
3. Sodium Lauryl Sulphate 1.47%
4. Maize Starch 3.24%
5. Purified Water QS
6. Zinc Sulphate Monohydrate 3.27%
7. Maize Starch 0.70%
8. Purified Talc 0.76%
9. Magnesium Stearate 0.88%
10. Colloidal Anhydrous Silica 0.35%
11. Lactose (Spray dried) 11.94%
12. Calcitriol Solution* 0.029%
13. Industrial Methylated Spirit QS
14. Lake of Quinoline Yellow 0.029%
15. Microcrystalline Cellulose (pH 102) 2.35
Total 100%

PART I:- Calcium Carbonate Granules
1. Sift Calcium Carbonate, Sodium Starch Glycolate,Sodium Lauryl Sulphate through 40#. Mix well for few minutes
2. Keep Purified water for boiling. Disperse Maize starch in Purified water and prepared slurry. Prepare Starch Paste by adding Maize starch slurry in boiling water
3. Granulate step 1 with step 2.
17

4. Pass the wet mass through 10#
5. Keep the granules for drying.
6. Pass the dried granules through 16#.
7. Pass Maize Starch, Purified Talc, Magnesium stearate through 40#
8. Mix step 6 to step 7.
PART II:-Calcitriol Granules
9. Prepare Calcitriol solution along with Industrial Methylated spirit (Calcitriol
Solution: Calcitriol in Brand : Labrafac CC + Butylated Hydroxy Anisole + Butylated
Hydroxy Toluene)
10. Adsorb the Calcitriol solution of Lactose (Spray dried) .Air dry.
11. Sift Lake of Quinoline Yellow through 100#.
12. Mix step 11 to step 10.
PART III:- Zinc Granules
13. Sift Zinc Sulphate, Microcrystalline cellulose (pH 102), Lactose (Spray Dried)
through 30#
14. Sift Purified Talc and Magnesium Stearate through 40#.
15. Mix well step 13 to step 14.
16. Place part I granules, simultaneously part II & III granules & Carry out compression achieve Triple Layered tablet by 18X8.5 mm Oval shaped punches BL/PL.
18

PPM (Part Per Million) of Calcitriol Solution Components but not limited to in each dosage form as given in the table below:
Table - 9

PPM Against the Final Weight of Tablet
Dosage Form Film coated Tablet (Example -1) Tablet in Tablet (Example - 2) Bilayered Tablet (Example - 3) Triple Layered (Example - 4)
Tablet Weight 1468 mg 1450 mg 1551 mg 1695 mg
Calcitriol 0.170 0.172 0.161 0.147
Labrafac CC 340.59 344.82 322.37 294.98
BHA 0.0681 0.0689 0.0644 0.0589
BHT 0.0340 0.0344 0.0322 0.0294
19

Claims:
1. Stabilized pharmaceutical composition comprising calcitriol, source of calcium, source of zinc, wherein the dosage form is either conventional tablet or multilayered tablet or tablet in tablet.
2. Stabilized pharmaceutical composition of tablet in tablet as claimed in claim 1, wherein the inner tablet comprises calcitriol, which is covered by the outer tablet comprising source of calcium and source of zinc.
3. Stabilized pharmaceutical composition of multilayered tablet as claimed in claim 1, wherein the tablet is of bilayered tablet comprising of one calcitriol layer and the other layer comprising of combination of source of calcium and source of zinc.
4. Stabilized pharmaceutical composition of multilayered tablet as claimed in claim 1, wherein the tablet is of triple layer tablet comprising of one calcitriol layer between a layer comprising of source of calcium and a layer comprising the source of zinc.
5. Stabilized pharmaceutical composition as claimed in claim 1, wherein calcitriol ranges from 0.1μg to 0.5 μg, source of calcium is calcium carbonate ranges fro 625 mg to 2500 mg, source of zinc is zinc sulphate monohydrate ranges from 15mg to 30mg and the stabilizer used are multi chain triglycerides.
6. Stabilized pharmaceutical composition as claimed in claims 1 to 4, wherein the calcitriol as solution incorporated into the dosage form as solution, butylated hydroxyl anisole, butylated hydroxyl toluene and stabilizer multi chain triglycerides.
7. Stabilized pharmaceutical composition of multilayered tablet as claimed in claim 1, wherein the bilayered tablet comprises calcium carbonate 80.59%,
20

zinc sulphate monohydrate 3.58% and calcitriol 0.1 to 0.5 μg/tablet and the triple layered tablet comprises calcium carbonate 73.74%., zinc sulphate monohydrate 3.27% and calcitriol 0.1 to 0.5 μg/tablet.
8. Stabilized pharmaceutical composition of conventional tablet as claimed in claim 1 and 4, wherein the film coated tablet comprises comprises calcium carbonate 85.15%, zinc sulphate monohydrate 3.78% and calcitriol 0.1 to 0.5 μg/tablet.
9. Stabilized pharmaceutical composition of tablet in tablet, wherein the inner tablet comprises comprises calcium carbonate 7.04% zinc sulphate monohydrate 0.31% and calcitriol 0.1 to 0.5 μg/tablet and outer tablet comprises calcium carbonate 78.11%, zinc sulphate monohydrate 3.47%.
10. Stabilized pharmaceutical composition as herein described with foregoing description and examples.
Dated this on 19th May 2006.

Ketana Laljibhai Babaria
For and on behalf of the applicant
21

Abstract
The present invention relates to a modified composition of calcitriol. The pharmaceutical composition comprises of calcitriol, calcium salt and zinc and/or their substitutes. Further this relates to the process for preparation of stabilized pharmaceutical compositions resulting therefrom. This dosage form is palatable and orally administrable formulation.
2 2 MAY 2006