FORM 2
THE PATENTS ACT, 1970 (39 of 1970)
PROVISIONAL SPECIFICATION (See section 10)
"A PHARMACEUTICAL COMPOSITION"

EMCURE PHARMACEUTICALS LIMITED, an Indian Company formed and registered under the Companies Act, 1956 and having its registered Office at EMCURE HOUSE, T-184, MIDC, Bhosari, Pune, Maharashtra, India
The following specification describes the nature of the invention.



Field of the invention:
The present invention relates to a stable pharmaceutical composition containing amlodipine and S-atenolol, methods of using the composition for treatment of cardiovascular disease such as myocardial infarction and hypertension.
Background of the invention:
Amlodipine and related dihydropyridine compounds are disclosed in U.S. Pat. No. 4,572,909, which is incorporated herein by reference, as potent antiischemic and antihypertensive agents. U.S. Pat. No.4,879,303, which is incorporated herein by reference, discloses amlodipine benzenesulfonate salt (also termed amlodipine besylate). Amlodipine and amlodipine besylate are potent and long lasting calcium channel blockers. As such, amlodipine, amlodipine besylate and other pharmaceutically acceptable acid addition salts of amlodipine have utility as antihypertensive agents and as antiischemic agents. Amlodipine and its pharmaceutically acceptable acid addition salts are also disclosed in U.S. Pat. No. 5,155,120 as having utility in the treatment of congestive heart failure. Amlodipine besylate is currently sold as Norvasc.RTM.
Atenolol is chemically known as: 4-[2-hydroxy-3-[(l-
methylethyl)amino]propoxy]benzeneacetamide). It is useful as beta-adrenergic blocker for the treatment of angina pectoris, arrhythmia and hypertension. It is also known that atenolol has l-aryloxy-3-aminopropan-2-ol nucleus wherein the hydroxy-bonded carbon is an asymmetric carbon and hence includes optical isomers, R- and S-isomers, and the S-isomer thereof is particularly useful as beta-adrenergic blocker in view of the superior pharmacological activities. It is reported that only S-isomer of atenolol has hypotensive activity and

activity on brachycardia (cf. A.A. Pearson, T. E. Gaffney, T. Walle, P. J. Privitera; J. Pharmacol. Exp. Ther., 250 (3), 759, 1989).
Various combination products of Amlodipine are available in the market, such as amlodipine and atorvastatin disclosed in US 6,486,182. However, no combination product employing the chiral form of both Amlodipine and Atenolol is available in the market.
It may be relevant to note that the characteristics of racemic Amlodipine and chirally pure S-Amlodipine are different e.g. chirally pure S-Amlodipine contains approx. 7% water whereas racemic contans approx. 0.5% water. The melting point of chirally pure S-Amlodipine is 68-72°C whereas that of racemic Amlodipine is approx 150 C. Similarly, the characteristics of Atenolol and S-atenolol are different. Thus, preparing a combination drug comprising chirally pure Atenolol and Amplodipine is a challenge.
Accordingly, formulation studies and stability studies were carried out for the designing such a formulation and various trials were also taken up. It was observed that two drugs when mixed together and compressed are incompatibile. In fact, S-Amlodipine disintegrated in the presence of S-atenolol.
Now, after a lot of studies and research, the Applicant has designed a formulation consisting of S- amlodipine and S-atenolol. The drug is a which is tablet-in-tablet type drug wherein the inner layer consists of S-amlodipine & the outer layer consists of S-atenolol. Whilst, the two incompatible drugs are separated from each other in storage condition, they are delivered to a patient as an unit dosage.

Description of the invention:
The present invention is directed to a pharmaceutical composition comprising a therapeutically effective amount of S-amlodipine and S-atenolol together with a pharmaceutically acceptable carrier, vehicle or diluent.
This invention is also directed to methods of treating myocardial infarction and hypertension in a mammal comprising administering to said mammal an effective amount of a the composition of the invention.
The composition of the invention utilizes S-isomer of a pharmaceutically acceptable salt of amlodipine such as hydrochloride, hydrobiomide, hydroiodide, nitrate, sulfate, bisulphate, besurate, succinate, inaleate, methanesulfonate, etc. The preferred S-isomer is of the besylate salt.
The said besylate salt may be prepared by methods known in the art, such as in US 4,879,303. The S-isomer of the salt is obtained by treatment of the salt with followed by crystallization and resolving the same.
The amlodipine used is also an S-isomer of the salt of the compound since the S-isomer is the most potent candidate for cardiac problems. The S-isomer is obtained from the salt of atenolol by conventional methods.
When the two drugs (S-amlodipine & S-atenolol) are mixed with the excipients and tablets are compressed using regular process, it was noted that after one month at 40°C there was degradation of S-amlosipine. Thus, one more incompatibility was observed between the two active ingredients itself. In order to resolve this, a special compression method was used. In this method, two separate granules

were prepared for S-amlodipine and S-atenolol. A special compression machine was used (Dry coata machine). The S-amlodipine granules are compressed using 6.0 mm punch into a small tablet with low hardness. This soft tablet is carried mechanically to the other turret wherein S-atenolol granules are compressed around it. Thus, in this final tablets, the low drugs are not mixed together. This gives physical separation of the drugs and avoids interaction.
The excipients in the present case need to be selected with great care since all the excipients are not compatible with S-amlodipine. Further, since this combination of S-amlodipine and S-atenolol has not been studied, no data is available on the same. In this case no ready data is available since the combination is neither studied nor marketed. The compatibility studies were carried out inhouse by mixing the drugs with excipients and exposing the mixtures to accelerated temperatures. After a fixed time interval, the samples were taken out and analysed. The studies were carried out on various excipients such as starch, lactose, microcrystalline cellulose, povidone K-30, sodium lauryl sulphate, crosscarmellose sodium, magnesium stearate, talc, hydrogenated castor oil. It was found that S-amlodipine was not compatible with lactose and hydrogenated castor oil. Finding out these incompatibilities was the first step. The preferred excipients that may be used in the composition are: Starch Pregelatinised Croscarmellose Sodium PVP K-30 Sodium lauryl Sulphate Collodial silicon dioxide Magnesium Stearate Talc Microcrystalline celluiose.
The composition of the invention may be prepared as a compressed tablet or capsule employing known techniques.

The amount of S-amlodipine may vary from 1.25 mg to 10 mg whereas the amount of S-atenolol may be 12.5 mg to 50 mg. The shelf life of the composition of the invention is about 20-28 months.
The invention is illustrated by the following examples which are illustrative only and not meant to restrict the scope of the invention in any manner:
Example 1 : Preparation of S-atenolol.
A mixture of (R)-epichlorohydrin ([a]D2 : -35.1 (neat),138.75 g, 1.5 mole) and water (82 ml) was cooled to -7 °C and to this cold reaction mixture is added a solution of 4-hydroxyphenyl acetamide of formula 1 (151.00 g, 1 mole) and benzyltrimethylammonium chloride (1.3 g) in sodium hydroxide [40 g, 1 mole; dissolved in water (670 ml)] with stirring over a period of 3 hrs. maintaining the temperature at -7 °C to -5 °C. The reaction mixture is then stirred further at -7 °C to -5 °C for 50 hrs. The precipitated solid is filtered, washed with water and dried at 60 °C to give 176 g of a mixture of S-glycidyl ether of formula 4 and S-chlorohydrin of formula 5 in about 3:2 ratio, m.p. 159-161 °C.
A mixture of isopropylamine (1.1 kg ) and water (200 ml) is cooled to 10 °C and a mixture of S-glycidyl ether of formula 4 and S-chlorohydrin of formula 5 obtained in Example 1 (176 g) is added to it in lots maintaining temperature between 10 to 15 °C over a period of 3 hrs. The reaction is then stirred further for another 10 hr. The excess of isopropylamine is removed by distillation and the residue was treated with the water. The slurry so obtained is acidified with 5N HC1 to pH 2.0. The resulting solution is then filtered, washed with water. The filtrate is basified with 2N NaOH to pH 11.7 and precipitated solid is filtered

washed with water and dried to get (S)-atenolol (206 g, 91%) in 99.1% ee
when analysed by using Chiracel OD column.
m.p. 152-153°C.
[Α]D25 : -17.2 (c= 1.0, 1N HC1).
IR : vmax 3352, 3168, 1635, 1242 cm'1.
1H NMR (DMSO-de): 8 0.99 (d, J= 7 Hz, 6H, 2 x CH3), 2.60 (m, 1H, CH),
2.74 (m, 2H, CH2), 3.27 (s, 2H, CH2), 3.88 ( m, 4H, CH2, CH, NH), 6.83 (d,
J = 8 Hz, 2H, Ar-H), 7.14 (d, J = 8 Hz, 2H, Ar-H), 7.40 (bs, 1H). 13C NMR
(DMSO-d6) : 22.01, 22.09, 41.26, 48.39, 49.38, 67.73, 70.58, 114.16,
128.41, 129.93, 157.17, 172.59 ppm.
Example 2 : Preparation of S-amlodipine.
The preparation of S-amlodipine is as described in US 6608206. S(-)Amlodipine-besvlate from S(-)-Amlodipine:
S(-) Amlodipine (62 gms, 0.152 moles, 93.1 ee) was dissolved in isopropanol (62 ml) and a solution of benzene sulfonic acid (24 gm, 0.152 moles) in 50 ml water was added maintaining the temperature .about.20.degree. C. The reaction mixture was stirred for 30 min. and distilled water (450 nil) was added. The besylate salt separated after 20 min. stirring continued for one hr. and the slurry was filtered. Washed with distilled water, hexane. The solid was dried under vac. at 40.degree. C. till constant wt. to give S(-) Amlodipine besylate (83 gm, 89% yield) 93.3 ee.
Recrystallisation of S(-) Amlodipine besylate
S(-) Amlodipine besylate (80 gms., 93.1 ee) was dissolved in isopropanol (80 ml) The reaction mixture was stirred for 30 min. and distilled water (640 ml) was added. The besylate salt separated after 20 min. stirring continued for one hr. and the slurry was filtered. Washed with distilled

water, hexane. The solid was dried under vacuo at 40.degree. C. till
constant wt. to give S(-) Amlodipine besylate (63 gm, 98.43 ee).
Example 3 : Preparation of composition of the invention.
Core tablet:
S-Amlodipine Besylate 3.6 mg (Eq. to 2.5 mg)
Croscarmellose Sodium 5.0 mg
Colloidal silicon dioxide 1.0 mg
Magnesium Stearate 2.0 mg
Microcrystalline cellulose q.s. 60.0 mg
Coat tablets:
S-atenolol 25.0 mg
Croscarmellose Sodium 8.0 mg
Colloidal silicon dioxide 3.0 mg
Talc 2.0 mg
Starch 1500 60.0 mg
Magnesium Stearate 3.0 mg
Microcrystalline cellulose 115.0mg
Process for core tablets:
All the aforesaid ingredients are mixed except for Magnesium stearate in a double cone blender. Magnesium Stearate is added later and mixed for 2 mins.
Process for coat tablets
Mix all ingredients except for Magnesium stearate and Talc in a double cone blender. Add Magnesium Stearate and Talc and mix for 2 mins.
A special compression machine was used (Dry coata machine). The S-amlodipine granules are compressed using 6.0 mm punch into a small tablet with low hardness. This soft tablet is carried mechanically to the other turret wherein S-Atenolol granules are compressed around it. Thus, in this final tablets, the two drugs are not mixed together. This gives physical separation of the drugs and avoids interaction.

Example 4 : Activity Chart:
Activity of S- Atenolol:
♦ Human studies have unequivocally shown that the (S)-Atenolol almost exclusively possesses the β1-blocking activity. The R -enantiomer do not contribute to this effect. (Stoschitzky K, Egginger G, Zernig G, et al. Chirality. 1993;5(l):15-9._
♦ S-atenolol 50mg produces similar reduction in blood pressure as compared to that of Atenolol lOOmg. (Clementi WA, Garvey TQ, Clifton GD, et al. Chirality. 1994;6:169-74)
♦ S- atenolol 50 mg produces similar reduction in heart rate after exercise to that of atenolol 100 mg. (Stoschitzky K, Lindner W, Klein W. Stereoselective release of (S)-atenolol from adrenergic nerve endings at exercise. Lancet. 1992 Sep 19;340(8821):696-7.)
♦ Lowered heart rate (BRADYCARDIA) is sometimes encountered after
administration of racemic atenolol, but the use of (S)-Atenolol avoids
this side effect (Kitaori K, Takehira Y, Furokawa Y, et al. Chem Pharm
Bull 1998, 46(3):505)
Activity of S- Amlodipine:
♦ S- Amlodipine, the chirally pure form of amlodipine is 1000 times
more stereoselective for the Di-hydropyridine receptor than R-
amlodipine. (Laufen H, Leitold M.. Chirality 1994;6(7):531-6)
♦> S- Amlodipine 2.5 mg has comparable efficacy as that of racemic amlodipine 5mg in the treatment of hypertension. (Hiremath Ms, Dighe GD.. JAMA India Aug 2002; 1: 86-92; Kerkar PG. Indian Journal of Clinical Practiue April 2003; 13: 49-54)

♦ S- Amlodipine is ideal as a switch over therapy in patients presenting peripheral edema with racemic amlodipine. (JAMA India Aug 2003; 2: 87-92)
♦ S- Amlodipine reduces serum total cholesterol, and triglyceride levels.(Hiremath Ms, Dighe GD.. JAMA India Aug 2002; 1: 86-92)
Activity of composition of invention:
♦ Amlodipine in combination with atenolol has been shown to be an effective and well-tolerated agent for treatment of mild-to-moderate hypertension. (Tyler HM. J Hum Hypertens 1991 Aug;5 Suppl 1:61-6 ; Burris JF, Ames RP, Applegate WB, Ram CV, Davidov ME, Mroczek WJ Cardiovasc Pharmacol 1988;12 Suppl 7:S98-102 )
♦ Clinical trials have proven the efficacy of a combination of amlodipine with atenolol in the management of angina pectoris (Frishman WH, Glasser S, Stone P, Deedwania PC, Johnson M, Fakouhi TD. Am J Cardiol 1999 Feb 15;83(4):507-14
♦ The combination of amlodipine and atenolol is effective than either of the drugs given alone in the treatment of angina (Davies RF, Habibi H, Klinke WP, Dessain P, Nadeau C, Phaneuf DC, Lepage S, Raman S, Herbert M, Foris K, et al J Am Coll Cardiol 1995 Mar 1,25:619-25 )
♦ Thus a fixed dose combination of S-amlodipine and atenolol can be very beneficial in the management of hypertension and angina.
The composition of the invention exhibits surprising activity greater than that of S-atenolol and S-amlodipine. This shows that the composition of the invention is synergistic.

Example 5 : Case studies showing use of composition for treatment
of hypertension/cardiac problems. Case study:
A 47 year old man with clinically proven stage II hypertension was treated with amlodipine alone. Failure to control hypertension caused the physician to switch therapy to the combination of S- amlodipine and S-atenolol. Patient responded to therapy with the combination of S-amlodipine and S-atenolol.

We claim:
1. A pharmaceutical composition comprising a therapeutically effective amount of S-amplodipine and S-atenolol and useful in the treatment of hypertension and cardiac diseases.
2. A composition as claimed in claim 1 wherein the amount of S-Atenolol is 12.5 mg to 50mg.
3. A composition as claimed in claim 1 wherein the amount of S-Amlodipine is 1.25 mg to lOmg.
4. A composition as claimed in claim 1 further consisting of excipients selected from starch pregelatinised, croscarmellose sodium, PVP K-30, sodium lauryl sulphate, magnesium stearate, talc and microcrystalline cellulose.
5. A composition substantially as hereindescribed and illustrated.
Dated this 6th day of March, 2004.
Rajeshwari H
Of K & S Partners
Attorney for Applicant