WO2020041864A1 - Synchronize hypertensive therapy with circadian rhythm - Google Patents

Abstract

The present invention is to provide a preparation which comprises a compounds having angiotensin II receptor antagonist such as Telmisartan, diuretic such as Chlorthalidone and calcium channel blocker such as Cilnidipine activity, which is highly stable and active and shows angiotensin II receptor antagonistic activity, diuretic and calcium channel blocking activities while maintaining circadian rhythm of blood pressure for a long time.

Description

Synchronize Hypertensive therapy with Circadian Rhythm

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to, and the benefit of, U.S. Provisional Application No. 62/722,881 , filed 08/25/2018, the contents of which are incorporated herein by reference in their entirety.

BACKGROUND

Field of the Invention:

The present invention relates to a pharmaceutical composition, more specifically a unique formulation and pharmaceutical composition that can manifest more excellent blood pressure lowering effect through synergism of three active ingredients, namely, Telmisartan, Chlorthalidone and Cilnidipine and can used for targeting the circadian rhythm of hypertension and treat resistant hypertension.

Description of the Related Art:

SUMMARY

The present invention relates to a drug combination capable of reducing risk in onset, particularly likely in the morning, of various diseases ascribable to vascular problems, such as cardiovascular or cerebrovascular problems, caused by circadian variation of blood pressure, in individuals with a blunted decline in blood pressure from night to early morning, i.e., so-called "non-dippers", in particular, normotensive individuals with normal 24-hour mean blood pressure among them.

The objective of the invention is thus to provide a new pharmaceutical composition containing a stable form of Telmisartan, Chlorthalidone and Cilnidipine which complies with the abovementioned stringent requirements imposed on a pharmaceutically active substance.

We have found that the combination of Telmisartan, Chlorthalidone and Cilnidipine provides a useful and unexpectedly advantageous combination for the treatment of cardiovascular disorders, such as hypertension, atherosclerosis and ischaemic heart disease.

In particular it has now been found that by combining Telmisartan, Chlorthalidone and Cilnidipine synergistic antihypertensive effect is achieved. It is a feature of this invention that the use of such a drug combination will provide one or more of the following effects: synergistic antihypertensive effects, antihypertensive effect over a longer period and/or allow a better management of any potential drug-related side effects. Furthermore, the improvement of blood pressure control achieved by using such a drug combination may afford a better protection from the associated diseases which are induced by hypertension.

The Rationale behind fixed-dose combination of Cilnidipine/ Telmisartan/

Chlorthalidone.

The cilnidipine/telmisartan/chlorthalidone fixed-dose combination provides the following advantages over other drug combinations for the following reasons.

1. Calcium channel blocker (CCB) - Angiotensin II Receptor Blockers (ARB), ARB - Thiazide are both preferred type of antihypertensive combination therapies and therefore CCB-ARB-Thiazide provides a preferred combination with synergistic blood pressure lowering effects.

2. The risk of hypokalemia or hyperkalemia is diminished by the combination as well as the risk for metabolic side effects such as hyperglycemia and hyperlipidemia.

3. The combination is especially beneficial to diabetic patients with cardioprotective and renoprotective effects of cilnidapine and telmisartan, overcoming the development of resistant hypertension in diabetic patients who are non-dippers or even nocturnal blood pressure risers and improving insulin sensitivity.

4. The pharmacokinetic profiles of the 3 drugs in the combination allows for sustained 24-48 hours blood pressure lowering effects with lower risk of hypotension and improved patient compliance and adherence.

5. The combination is unique in that it provides immediate risk reduction of cardiovascular complications from the time of treatment commencement. 6. Cilnidipine reduces the risk of any hyperuricemia induced by chlorthalidone, cilnidipine and telmisartan prevent the renin-angiotensin- aldosterone system (RAAS) activation synergistically.

7. The clinical effects of the triple combination are pharmacologically equivalent to a 5 drug combination therapy: A beta blocker, a thiazide diuretic, an ARB, a CCB and a direct vasodilator (cilnidipine causes more vasodilation in renal arteries than any other CCB)

8. Patients who will likely benefit from the combination include: patients with resistant hypertension who fail other therapies, patients with fluctuations in blood pressure, patients with white coat hypertension or morning hypertension, patients with ischemic heart diseases, diabetic patients, patients with heart failure, patients with a history of ischemic strokes, patients with high risk for QT prolongation, patients with chronic kidney disease and patients with the metabolic syndrome.

9. The combination is unique in being suitable as a first line treatment for eligible patients and as a rescue treatment when other treatments fail.

10. The combination resists future changes to the blood pressure lowering effects by endogenous compensatory mechanisms such as RAAS and sympathetic activation.

11. Low risk of drug-drug interactions and drug-food interactions. All 3 drugs are active and are independent of hepatic activation. The combination provides great benefits in case of chronic kidney disease.

12. The combination can be manufactured as an immediate release formulation due to the sustained blood pressure lowering effects of the combination.

BRIEF DESCRIPTION OF THE DRAWINGS

The details of one or more embodiments of the invention are set forth in the accompanying drawings and the description below.

FIGURE 1 : A bilayer Tablet design

FIGURE 2: Dissolution results of Chlorthalidone in the formulation shown in TABLE

13A

FIGURE 3 Dissolution results of Telmisartan in the formulation shown in TABLE 13A

FIGURE 4 Dissolution results of Cilinidpine in the formulation shown in TABLE 13A. FIGURE 5: Effect of tablet weight using same formulation for immediate release bilayer tablet and for DR tablet in capsule formula (Cilindipine). Composition related to TABLE 14A and results shown in TABLE 14B. Results related to Example 10 study.

FIGURE 6: Effect of tablet weight using same formulation for immediate release bilayer tablet and for DR tablet in capsule formula (Telmisartan). Composition related to TABLE 14A and results shown in TABLE 14C. Results related to Example 10 study. FIGURE 7: Effect of tablet weight using same formulation for immediate release bilayer tablet and for DR tablet in capsule formula (Chlorthalidone. Composition related to TABLE 14A and results shown in TABLE 14D. Results related to Example 10 study. FIGURE 8: Process flow chart:

FIGURE 9A: Manufacturing process.

FIGURE 9B: Continous of manufacturing process shown in FIGURE 8A.

DETAILED DESCRIPTION

There is a well-established circadian variation in frequency of onset of cardiovascular events including ventricular arrhythmias, stroke, angina, and myocardial infarction. The peak frequency of such events is exhibited in the morning hours, theoretically in conjunction with the morning surge in systolic blood pressure and heart rate. There is also some evidence of a secondary peak in frequency of such events in the late afternoon or evening hours. Current anti-hypertensive medications do not appear to attenuate early morning increases in blood pressure observed in hypertensive patients. Thus it would be physiologically advantageous to design an anti-hypertensive pharmaceutical composition to the typical circadian patterns of blood pressure and heart rate.

Hypertension is a cause of heart disease and other related cardiac co-morbidities. Hypertension occurs when blood vessels constrict. As a result, the heart works harder to maintain flow at a higher blood pressure, which can contribute to heart failure. A large segment of the general population, as well as a large segment of patients implanted with pacemakers or defibrillators, suffer from hypertension. The long term mortality as well as the quality of life can be improved for this population if blood pressure and hypertension can be reduced. Many patients who suffer from hypertension do not respond to treatment, such as treatments related to lifestyle changes and hypertension drugs. A unit dosage form, such as a tablet or capsule or the like for delivering drugs into the body in a circadian release fashion, is comprising of one or more populations of Telmisartan, Chlorthalidone and Cilnidipine -containing particles (beads, pellets, granules, etc.). Each bead population exhibits a pre-designed rapid or sustained release profile with or without a predetermined lag time of 3 to 6 hours. Such a circadian rhythm release cardiovascular drug delivery system is designed to provide a plasma concentration-time profile for the 3 drugs, which fit the physiological need of blood pressure lowering during the day, i.e., mimicking the circadian rhythm and severity/manifestation of a cardiovascular disease, predicted based on pharmaco- kinetic and pharmaco-dynamic considerations and in

A major objective for effective treatment of cardiovascular diseases is to deliver the drug in higher concentrations during the time of greatest need, typically during the early morning hours, and in lesser concentrations when the need is less, such as during the late evening and early sleep hours. This can be accomplished by administration of the triple therapy dosage form of the present invention, which relates to release of Telmisartan, Chlorthalidone and Cilnidipine from dosage forms. The dosage form of the present invention is designed to release Telmisartan, Chlorthalidone and Cilnidipine with resulting plasma concentration(s) of Telmisartan, Chlorthalidone and Cilnidipine complete each other in a circadian rhythm fashion following administration of a single dosage form at bedtime, thereby minimizing potential risks of a cardiovascular disease, such as stroke, heart attack and myocardial infarction, decreasing systolic blood pressure, or reducing hypertension or beta-adrenergic stimulation, treating cardiac arrhythmia, hypertrophic subaortic stenosis or angina, or preventing migraine and thus enhancing patient compliance and therapeutic efficacy, while reducing cost of treatment.

The dosage forms of the present invention, are novel formulations designed to provide reductions in blood pressure and heart rate over 24 hours, including optimal protection in the early morning hours when patients are most vulnerable to cardiovascular events i.e., in a circadian rhythm fashion to effectively treat cardiovascular diseases. At steady state, blood levels of the composition begin to increase approximately 4 hours after bedtime administration of these dosage forms such as tablets and rise progressively over the early morning hours to reach peak plasma concentrations approximately 14 hours after dosing. These tablets produce peak plasma levels that rise slowly to attenuate the rapid increase in blood pressure and heart rate that precedes and follows waking. This increase is associated with circadian variation in catecholamine secretion and in rennin release. The rise in plasma concentration after dosing with these formulations parallel the circadian rise in morning blood pressure associated with target organ damage in patients with hypertensive and ischemic cardiovascular disease.

The present invention is applied to multi-dose forms, i.e., drug products in the form of multi-particulate dosage forms (pellets, beads, granules or mini-tablets) or in other forms suitable for oral administration.

The following non-limiting examples illustrate the tablet dosage forms manufactured in accordance with the invention, which exhibit in vitro drug release profiles, similar to that predicted by performing modeling exercises, and in vivo plasma concentrations following circadian rhythm pharmaco-dynamic profile of angina attacks. Such dosage forms when administered at bed time would enable maintaining drug plasma concentration at a level potentially beneficial in minimizing the occurrence of heart attacks in the early hours of the morning.

Telmisartan

Telmisartan is an angiotensin antagonist, particularly an angiotensin II antagonist which, by virtue of its pharmacological properties, may be used, for example, to treat hypertension and cardiac insufficiency, to treat ischemic peripheral circulatory disorders and myocardial ischaemia (angina), to prevent the progression of cardiac insufficiency after myocardial infarct, and to treat diabetic neuropathy, glaucoma, gastrointestinal diseases and bladder diseases.

Pharmacokinetics of Telmisartan

Following oral administration, peak concentrations (Cmax) of telmisartan are reached in 0.5 to 1 hour after dosing. Food slightly reduces the bioavailability of telmisartan, with a reduction in the area under the plasma concentration-time curve (AUC) of about 6% with the 40 mg tablet and about 20% after a 160 mg dose. The absolute bioavailability of telmisartan is dose dependent. At 40 and 160 mg the bioavailability is 42% and 58%, respectively. The pharmacokinetics of orally administered telmisartan are nonlinear over the dose range 20 to 160 mg, with greater than proportional increases of plasma concentrations (C.sub.max and AUC) with increasing doses. Telmisartan shows bi- exponential decay kinetics with a terminal elimination half-life of approximately 24 hours. Trough plasma concentrations of telmisartan with once daily dosing are about 10 to 25% of peak plasma concentrations. Telmisartan has an accumulation index in plasma of 1.5 to 2.0 upon repeated once daily dosing.

Drug metabolism

Telmisartan is metabolised by conjugation to the glucuronide of the parent compound. No pharmacological activity has been shown for the conjugate.

Elimination

Telmisartan is characterised by biexponential decay pharmacokinetics with a terminal elimination half-life of >20 hours. The maximum plasma concentration (Cmax) and, to a smaller extent, the area under the plasma concentration-time curve (AUC), increase disproportionately with dose. There is no evidence of clinically relevant accumulation of Telmisartan taken at the recommended dose. Plasma concentrations were higher in females than in males, without relevant influence on efficacy.

After oral (and intravenous) administration Telmisartan is nearly exclusively excreted with the feces, mainly as unchanged compound. Cumulative urinary excretion is <1 % of dose. Total plasma clearance (Cltot) is high (approximately 1 ,000 ml/min) compared with hepatic blood flow (about 1 ,500 ml/min).

Distribution

Telmisartan is largely bound to plasma protein (>99.5 %), mainly albumin and alpha-1 acid glycoprotein. The mean steady state apparent volume of distribution (Vdss) is approximately 500.

Telmisartan is unique among other angiotensin II receptor blockers in having the following characteristics.

I. It has a half-life of 24 hours which is longer than most ARBs.

II. It is FDA approved for the prevention of cardiovascular risk and mortality.

III. In addition to its anti-hypertensive effect through antagonizing AT1 receptors, telmisartan has a unique property that activates peroxisome proliferator-activated receptor-y (PPAR-g) and is suggested to improve insulin sensitivity and reduce triglyceride levels, leading to a reduction of the risk for atherosclerosis. IV. A 12 weeks of treatment with telmisartan (in exchange for valsartan or candesartan) resulted in significant decreases in fasting insulin, fasting blood glucose, hemoglobin A1c and triglycerides; and increases in high density lipoprotein cholesterol and adiponectin, suggesting a potential metabolic and anti- atherogenic benefit.

V. Telmisartan may accelerate reverse cholesterol transport or inhibit net cholesterol absorption through activation of ABC1, leading to lowering of TC and Low density lipids-Cholesterol (23). These results suggest that telmisartan may have the ability to lower cholesterol. Thus using a telmisartan alone or in combination with a diuretic/CCB can be efficacious in patients with dyslipidemia.

Chlorthalidone

The following are unique characteristics to chlorthalidone making it quite desirable in fixed dose combinations of antihypertensive therapies.

I. It is the most effective among thiazide diuretics and thiazide-like diuretics in lowering the blood pressure.

II. Chlorthalidone has a half-life of 40 hours and provides more consistent 24-hr blood pressure lowering effects than hydrochlorothiazide.

III. Lower risk of hyperglycemia, dyslipidemia and hypokalemia at doses of 12.5 and 25 mg than equipotent doses of other thiazide diuretics. For example, even though chlorthalidone is considered to have twice the efficacy of hydrochlorothiazide, 12.5 and 25 mg doses of chlorthalidone result in lower metabolic side effects than 25 and 50 mg of hydrochlorothiazide, respectively.

Pharmacokinetics: After an oral dose about 65% is absorbed. Peak serum levels are reached 2-6 hours after administration. Most of the absorbed dose (98%) is bound to red cell carbonic anhydrase. The plasma half-life is 50-90 hours during long term treatment 30-60% of the dose is excreted unchanged in the urine and up to 10% is excreted in the faeces. No metabolites have been identified.

Cilnidipine

Cilnidipine is a unique Ca2+ channel blocker with equipotent inhibitory actions on the L- type Ca2+ channels in the heart and vascular system and the N-type Ca2+ channels, located in adrenergic neurons. In fact, cilnidipine has been clarified to exert antisympathetic actions, unlike any other classical Ca2+ channel blockers. Interestingly, renoprotective and neuroprotective effects as well as cardioprotective action of cilnidipine have been demonstrated in a vast number of preclinical and clinical studies.

Cilnidipine has a half-life of about 5 hours but its hypotensive effects are unique compared to other CCBs and other antihypertensive agents. The onset of action is slow but the effects are long lasting. Hence, the drug provides a unique combination of lower risk for hypotension yet sustained effective lowering of blood pressure in hypertensive patients.

Absorption: Bioavailability is 64-90%. Peak Plasma Concentration6-12 hour following oral administration.Tmax =2 hr,cmax(ng/ml) =8.9±4.2, ,AUCinf(ng h/mL)=41.2±20.4 Metabolism

Metabolized extensively (90%) by liver to inactive metabolites via the cytrochrome P450 (3A4) iso- enzyme.

Cilnidipine was rapidly metabolized to three metabolites by (CYP3A) after

administration of 10 mg of cilnidipine.

M1 Dehydrogenated metabolite of dihydropyridine ring of cilnidipine

M2 Demethylation metabolite of lateral chain of dihydropyridine ring of cilnidipine.

M3 Dehydrogenation and demethylation metabolite of cilnidipine

Excretion: Mainly by urine; CL (L/hr.)=304.7±147.5

The pharmacological effects and advantages of each drug summaraized as the following:

The composition can be administered in pharmaceutically acceptable solutions, which may routinely contain pharmaceutically acceptable concentrations of salt, buffering agents, preservatives, compatible carriers, adjuvants, and optionally other therapeutic agents.

Oral Administration The compositions of the described invention may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules or syrups or elixirs. For oral administration in the form of tablets or capsules, the active drug components may be combined with any oral non-toxic pharmaceutically acceptable inert carrier, such as lactose, starch, sucrose, cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, talc, mannitol, ethyl alcohol (liquid forms) and the like.

Moreover, when desired or needed, suitable binders, lubricants, disintegrating agents and coloring agents also may be incorporated in the mixture. Powders and tablets may be comprised of from about 5 to about 95 percent of the composition. Suitable binders include starch, gelatin, natural sugars, corn sweeteners, natural and synthetic gums such as acacia, sodium alginate, carboxymethylcellulose, polyethylene glycol and waxes. Among the lubricants there may be mentioned for use in these dosage forms, boric acid, sodium benzoate, sodium acetate, sodium chloride, and the like. Disintegrants include starch, methylcellulose, guar gum and the like.

Compositions intended for oral use can be prepared according to any known method, and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents, and preserving agents in order to provide pharmaceutically elegant and palatable preparations.

Tablets may contain the active ingredient(s) in admixture with non-toxic pharmaceutically-acceptable excipients which are suitable for the manufacture of tablets. These excipients may be, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch or alginic acid; binding agents, for example, starch, gelatin or acacia; and lubricating agents, for example, magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques, for example, to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period, to protect the composition from oxidation or photodegradation; or for controlled release. For example, a time delay material such as glyceryl monostearate or glyceryl distearate can be employed.

Compositions of the described invention also may be formulated for oral use as hard gelatin capsules, where the active ingredient(s) is(are) mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or soft gelatin capsules wherein the active ingredient(s) is (are) mixed with water or an oil medium, for example, peanut oil, liquid paraffin, or olive oil.

Liquid form preparations include solutions, suspensions and emulsions wherein the active ingredient(s) is (are) in admixture with excipients suitable for the manufacture of aqueous suspensions and emulsions. Such excipients are suspending agents: sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth, and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide such as lecithin, or condensation products of an alkylene oxide with fatty acids, for example, polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example, heptadecaethyl-eneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. As an example may be mentioned water or water-propylene glycol solutions for parenteral injections or addition of one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin and pacifiers for oral solutions, suspensions and emulsions.

Compositions of the described invention may be formulated as oily suspensions by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil, such as liquid paraffin. The oily suspensions may contain a thickening agent, for example, beeswax, hard paraffin or cetyl alcohol. Sweetening agents, such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions can be preserved by the addition of an antioxidant such as ascorbic acid. Compositions of the described invention may be formulated in the form of dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water. The active ingredient in such powders and granules is provided in admixture with a dispersing or wetting agent, suspending agent, and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example, sweetening, flavouring and colouring agents also can be present.

The compositions of the invention also may be in the form of an emulsion. An emulsion is a two-phase system prepared by combining two immiscible liquid carriers, one of which is disbursed uniformly throughout the other and consists of globules that have diameters equal to or greater than those of the largest colloidal particles. The globule size must be such that the system achieves maximum stability. Usually, separation of the two phases will not occur unless a third substance, an emulsifying agent, is incorporated. Thus, a basic emulsion contains at least three components, the two immiscible liquid carriers and the emulsifying agent, as well as the active ingredient. Most emulsions incorporate an aqueous phase into a non-aqueous phase (or vice versa). However, it is possible to prepare emulsions that are basically non-aqueous, for example, anionic and cationic surfactants of the non-aqueous immiscible system glycerin and olive oil. Thus, the compositions of the invention may be in the form of an oil-in-water emulsion. The oily phase can be a vegetable oil, for example, olive oil or arachis oil, or a mineral oil, for example a liquid paraffin, or a mixture thereof. Suitable emulsifying agents may be naturally-occurring gums, for example, gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the partial esters with ethylene oxide, for example, polyoxyethylene sorbitan monooleate. The emulsions also may contain sweetening and flavoring agents.

The compositions of the invention also may be formulated as syrups and elixirs. Syrups and elixirs may be formulated with sweetening agents, for example, glycerol, propylene glycol, sorbitol or sucrose. Such formulations also may contain a demulcent, a preservative, and flavouring and colouring agents. Demulcents are protective agents employed primarily to alleviate irritation, particularly mucous membranes or abraded tissues. A number of chemical substances possess demulcent properties. These substances include the alginates, mucilages, gums, dextrins, starches, certain sugars, and polymeric polyhydric glycols. Others include acacia, agar, benzoin, carbomer, gelatin, glycerin, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, propylene glycol, sodium alginate, tragacanth, hydrogels and the like.

For buccal administration, the compositions of the described invention may take the form of tablets or lozenges formulated in a conventional manner.

There are three general methods of tablet preparation: the wet-granulation method; the dry-granulation method; and direct compression. The method of preparation and the added ingredients are selected to give the tablet formulation the desirable physical characteristics allowing the rapid compression of tablets. After compression, the tablets must have a number of additional attributes such as appearance, hardness, disintegration ability, appropriate dissolution characteristics, and uniformity, which also are influenced both by the method of preparation and by the added materials present in the formulation.

According to some embodiments, the tablet is a compressed tablet. Compressed tablets are solid dosage forms formed with pressure and contain no special coating. Generally, they are made from powdered, crystalline, or granular materials, alone or in combination with binders, disintegrants, controlled-release polymers, lubricants, diluents and colorants.

According to some embodiments, the tablet is a sugar-coated tablet. These are compressed tablets containing a sugar coating. Such coatings may be colored and are beneficial in covering up drug substances possessing objectionable tastes or odors and in protecting materials sensitive to oxidation.

According to some embodiments, the tablet is a film-coated tablet. These compressed tablets are covered with a thin layer or film of a water-soluble material. Numerous polymeric substances with film-forming properties may be used.

According to some embodiments, the tablet is a multiple compressed tablet. These tablets are made by more than one compression cycle. Layered tablets are prepared by compressing additional tablet granulation on a previously compressed granulation. The operation may be repeated to produce multilayered tablets of two or three layers. Press-coated tablets (dry-coated) are prepared by feeding previously compressed tablets into a special tableting machine and compressing another granulation layer around the preformed tablets.

According to some embodiments, the tablet is a controlled-release tablet. Compressed tablets can be formulated to release the drug slowly over a prolonged period of time. Hence, these dosage forms have been referred to as prolonged-release or sustained- release dosage forms.

Non-Oral Administration

The term "non-oral administration" represents any method of administration in which a composition is not provided in a solid or liquid oral dosage form, wherein such solid or liquid oral dosage form is traditionally intended to substantially release and or deliver the drug in the gastrointestinal tract beyond the mouth and/or buccal cavity. Such solid dosage forms include conventional tablets, capsules, caplets, etc., which do not substantially release the drug in the mouth or in the oral cavity. It is appreciated that many oral liquid dosage forms such as solutions, suspensions, emulsions, etc., and some oral solid dosage forms may release some of the drug in the mouth or in the oral cavity during the swallowing of these formulations. However, due to their very short transit time through the mouth and the oral cavities, the release of drug from these formulations in the mouth or the oral cavity is considered de minimus or insubstantial. Accordingly, it is understood that the term "non-oral" includes parenteral, transdermal, inhalation, implant, and vaginal or rectal formulations and administrations. Further, implant formulations are to be included in the term "non-oral," regardless of the physical location of implantation. Particularly, implantation formulations are known which are specifically designed for implantation and retention in the gastrointestinal tract. Such implants are also considered to be non-oral delivery formulations, and therefore are encompassed by the term "non-oral."

Rectal Administration The compositions of the described invention may be in the form of suppositories for rectal administration of the composition, such as for treating pediatric fever. The terms "rectal" or "rectally" as used herein refer to introduction into the body through the rectum where absorption occurs through the walls of the rectum. These compositions can be prepared by mixing the drug with a suitable nonirritating excipient such as cocoa butter and polyethylene glycols which are solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum and release the drug. When formulated as a suppository the compositions of the invention may be formulated with traditional binders and carriers, such as triglycerides.

According to some embodiments, the tablet is a compressed suppository or insert. For preparing suppositories, a low melting wax such as a mixture of fatty acid glycerides, such as cocoa butter, is first melted, and the active ingredient is dispersed homogeneously therein by stirring or similar mixing. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool and thereby solidify.

Parenteral Administration

The compositions of the described invention may be in the form of a sterile injectable aqueous or oleaginous suspension. Injectable preparations, such as sterile injectable aqueous or oleaginous suspensions, may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.

The sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1 , 3-butanediol. A solution generally is considered as a homogeneous mixture of two or more substances; it is frequently, though not necessarily, a liquid. In a solution, the molecules of the solute (or dissolved substance) are uniformly distributed among those of the solvent. A suspension is a dispersion (mixture) in which a finely-divided species is combined with another species, with the former being so finely divided and mixed that it does not rapidly settle out. In everyday life, the most common suspensions are those of solids in liquid water. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For parenteral application, particularly suitable vehicles consist of solutions, preferably oily or aqueous solutions, as well as suspensions, emulsions, or implants. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension also may contain suitable stabilizers or agents, which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions. Alternatively, the active compounds may be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.

The active agent, when it is desirable to deliver it locally, may be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents. Pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form.

The pharmaceutical compositions also may comprise suitable solid or gel phase carriers or excipients. Examples of such carriers or excipients include, but are not limited to, calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols.

Suitable liquid or solid pharmaceutical preparation forms are, for example, microencapsulated, and if appropriate, with one or more excipients, encochleated, coated onto microscopic gold particles, contained in liposomes, pellets for implantation into the tissue, or dried onto an object to be rubbed into the tissue. Such pharmaceutical compositions also may be in the form of granules, beads, powders, tablets, coated tablets, (micro)capsules, suppositories, syrups, emulsions, suspensions, creams, drops or preparations with protracted release of active compounds, in whose preparation excipients and additives and/or auxiliaries such as disintegrants, binders, coating agents, swelling agents, lubricants, or solubilizers are customarily used as described above. The pharmaceutical compositions are suitable for use in a variety of drug delivery systems. For a brief review of methods for drug delivery, see Langer R. "New methods of drug delivery." Science. 249(4976): 1527- 1533 (1990), which is incorporated herein by reference.

Injectable depot forms are made by forming microencapsulated matrices of a described inhibitor in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of inhibitor to polymer and the nature of the particular polymer employed, the rate of drug release may be controlled. Such long acting formulations may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations also are prepared by entrapping the inhibitor of the described invention in liposomes or microemulsions, which are compatible with body tissues.

The locally injectable formulations may be sterilized, for example, by filtration through a bacterial-retaining filter or by incorporating sterilizing agents in the form of sterile solid compositions that may be dissolved or dispersed in sterile water or other sterile injectable medium just prior to use. Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation also may be a sterile injectable solution, suspension or emulsion in a nontoxic, parenterally acceptable diluent or solvent such as a solution in 1 ,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile, fixed oils conventionally are employed dr as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectable.

Formulations for parenteral administration include aqueous and non-aqueous sterile injection solutions that may contain anti-oxidants, buffers, bacteriostatic and solutes, which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions, which may include suspending agents and thickening agents. The formulations may be presented in unit-dose or multi-dose containers, for example sealed ampules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, saline, water-for-injection, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.

The pharmaceutical agent or a pharmaceutically acceptable ester, salt, solvate or prodrug thereof may be mixed with other active materials that do not impair the desired action, or with materials that supplement the desired action. Solutions or suspensions used for parenteral, intradermal, subcutaneous, intrathecal, or topical application may include, but are not limited to, for example, the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerin, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose. The parenteral preparation may be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic. Administered intravenously, particular carriers are physiological saline or phosphate buffered saline (PBS).

Delivery by Inhalation or Insufflation

The compositions of the described invention may be in the form of a dispersible dry powder for delivery by inhalation or insufflation (either through the mouth or through the nose). Dry powder compositions may be prepared by processes known in the art, such as lyophilization and jet milling, as disclosed in International Patent Publication No. WO 91/16038 and as disclosed in U.S. Pat. No. 6,921 ,527, the disclosures of which are incorporated by reference. The composition of the described invention is placed within a suitable dosage receptacle in an amount sufficient to provide a subject with a unit dosage treatment. The dosage receptacle is one that fits within a suitable inhalation device to allow for the aerosolization of the dry powder composition by dispersion into a gas stream to form an aerosol and then capturing the aerosol so produced in a chamber having a mouthpiece attached for subsequent inhalation by a subject in need of treatment. Such a dosage receptacle includes any container enclosing the composition known in the art such as gelatin or plastic capsules with a removable portion that allows a stream of gas (e.g., air) to be directed into the container to disperse the dry powder composition. Such containers are exemplified by those shown in U.S. Pat. Nos. 4,227,522; 4,192,309; and 4,105,027. Suitable containers also include those used in conjunction with Glaxo's Ventolin. RTM. Rotohaler brand powder inhaler or Fison's Spinhaler.RTM. brand powder inhaler. Another suitable unit-dose container which provides a superior moisture barrier is formed from an aluminum foil plastic laminate. The pharmaceutical-based powder is filled by weight or by volume into the depression in the formable foil and hermetically sealed with a covering foil-plastic laminate. Such a container for use with a powder inhalation device is described in U.S. Pat. No. 4,778,054 and is used with Glaxo's Diskhaler.RTM. (U.S. Pat. Nos. 4,627,432; 4,811,731 ; and 5,035,237). Each of these references is incorporated herein by reference.

Topical Administration

The compositions of the described invention also may be deliverable transdermal. The transdermal compositions may take the form of creams, lotions, aerosols and/or emulsions and can be included in a transdermal patch of the matrix or reservoir type as are conventional in the art for this purpose. The term "topical" refers to administration of an inventive composition at, or immediately beneath, the point of application. The phrase "topically applying" describes application onto one or more surfaces(s) including epithelial surfaces. Although topical administration, in contrast to transdermal administration, generally provides a local rather than a systemic effect, as used herein, unless otherwise stated or implied, the terms topical administration and transdermal administration are used interchangeably. For the purpose of this application, topical applications shall include mouthwashes and gargles.

Topical administration may also involve the use of transdermal administration such as transdermal patches or iontophoresis devices which are prepared according to techniques and procedures well known in the art. The terms "transdermal delivery system", transdermal patch" or "patch" refer to an adhesive system placed on the skin to deliver a time released dose of a drug(s) by passage from the dosage form through the skin to be available for distribution via the systemic circulation. Transdermal patches are a well-accepted technology used to deliver a wide variety of pharmaceuticals, including, but not limited to, scopolamine for motion sickness, nitroglycerin for treatment of angina pectoris, clonidine for hypertension, estradiol for post-menopausal indications, and nicotine for smoking cessation.

Patches suitable for use in the described invention include, but are not limited to, (1 ) the matrix patch; (2) the reservoir patch; (3) the multi-laminate drug-in adhesive patch; and (4) the monolithic drug-in-adhesive patch; TRANSDERMAL AND TOPICAL DRUG DELIVERY SYSTEMS, pp. 249-297 (Tapash K. Ghosh et al. eds., 1997), hereby incorporated herein by reference. These patches are well known in the art and generally available commercially.

Additional Components

The compositions of the described invention may further include conventional excipients, i.e., pharmaceutically acceptable organic or inorganic carrier substances suitable for parenteral application which do not deleteriously react with the active compounds. Suitable pharmaceutically acceptable carriers include, but are not limited to, water, salt solutions, alcohol, vegetable oils, polyethylene glycols, gelatin, lactose, amylose, magnesium stearate, talc, silicic acid, viscous paraffin, perfume oil; fatty acid monoglycerides and diglycerides, petroethral fatty acid esters, hydroxymethylcellulose, polyvinylpyrrolidone, etc.

The compositions may be sterilized and if desired, mixed with auxiliary agents, e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, colorings, flavoring and/or aromatic substances and the like which do not deleteriously react with the active compounds. For parenteral application, suitable vehicles include solutions, such as oily or aqueous solutions, as well as suspensions, emulsions, or implants.

Aqueous suspensions may contain substances which increase the viscosity of the suspension and include, for example, but not limited to, sodium carboxymethyl cellulose, sorbitol and/or dextran. Optionally, the suspension also may contain stabilizers. These compositions also may contain adjuvants including preservative agents, wetting agents, emulsifying agents, and dispersing agents. Prevention of the action of microorganisms may be ensured by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. It also may be desirable to include isotonic agents, for example, sugars, sodium chloride and the like. Prolonged absorption of the injectable pharmaceutical form may be brought about by the use of agents delaying absorption, for example, aluminum monostearate and gelatin.

Suspensions, in addition to the active compounds, may contain suspending agents, as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, tragacanth, and mixtures thereof.

The composition, if desired, also may contain minor amounts of wetting or emulsifying agents or pH buffering agents. Oral formulations can include standard carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate, etc. Examples of suitable buffering agents include, without limitation: acetic acid and a salt (1%-2% w/v); citric acid and a salt (1%~3% w/v); boric acid and a salt (0.5%-2.5% w/v); and phosphoric acid and a salt (0.8%-2% w/v). Suitable preservatives include benzalkonium chloride (0.003%-0.03% w/v); chlorobutanol (0.3%-0.9% w/v); parabens (0.01%-0.25% w/v) and thimerosal (0.004%-0.02% w/v).

Pharmaceutically Acceptable Carrier

The pharmaceutical compositions within the described invention contain a therapeutically effective amount of a rho kinase inhibitor compound and optionally other therapeutic agents included in a pharmaceutically-acceptable carrier. The components of the pharmaceutical compositions also are capable of being commingled in a manner such that there is no interaction which would substantially impair the desired pharmaceutical efficiency. The therapeutically effective amount of the rho kinase inhibitor compound may be provided in particles. The particles may contain the therapeutic agent(s) in a core surrounded by a coating. The therapeutic agent(s) also may be dispersed throughout the particles. The therapeutic agent(s) also may be adsorbed into the particles. The particles may be of any order release kinetics, including zero order release, first order release, second order release, delayed release, sustained release, immediate release, etc., and any combination thereof. The particle may include, in addition to the therapeutic agent(s), any of those materials routinely used in the art of pharmacy and medicine, including, but not limited to, erodible, nonerodible, biodegradable, or nonbiodegradable material or combinations thereof. The particles may be microcapsules that contain the therapeutic agent(s) in a solution or in a semi-solid state. The particles may be of virtually any shape.

Both non-biodegradable and biodegradable polymeric materials may be used in the manufacture of particles for delivering the therapeutic agent(s). Such polymers may be natural or synthetic polymers. The polymer is selected based on the period of time over which release is desired. Bioadhesive polymers of particular interest include bioerodible hydrogels as described by Sawhney, et al., the teachings of which are incorporated herein. Sawhney A S, et al., Macromolecules. 26(4): 581-587 (1993). These include polyhyaluronic acids, casein, gelatin, glutin, polyanhydrides, polyacrylic acid, alginate, chitosan, poly(methyl methacrylates), poly(ethyl methacrylates), poly(butylmethacrylate), poly(isobutyl methacrylate), poly(hexylmethacrylate), poly(isodecyl methacrylate), poly(lauryl methacrylate), poly(phenyl methacrylate), poly(methyl acrylate), poly(isopropyl acrylate), poly(isobutyl acrylate), and poly(octadecyl acrylate).

The therapeutic agent(s) may be contained in controlled release systems. In order to prolong the effect of a drug, it often is desirable to slow the absorption of the drug from subcutaneous, intrathecal, or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle. Use of a long-term sustained release formulations may be particularly suitable for treatment of chronic conditions. Long-term sustained release formulations are well- known to those of ordinary skill in the art and include some of the release systems described above.

Pharmaceutically Acceptable Salts

Depending upon the structure, the rho kinase inhibitor compound, and optionally at least one other therapeutic agent, may be administered per se (neat) or, depending upon the structure of the inhibitor, in the form of a pharmaceutically acceptable salt. TN-acetyl cysteine may form pharmaceutically acceptable salts with organic or inorganic acids, or organic or inorganic bases. When used in medicine the salts should be pharmaceutically acceptable, but non-pharmaceutically acceptable salts conveniently may be used to prepare pharmaceutically acceptable salts thereof.

By "pharmaceutically acceptable salt" is meant those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well-known in the art. For example, P. H. Stahl, et al. describe pharmaceutically acceptable salts in detail in "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" (Wiley VCH, Zurich, Switzerland: 2002).

The salts may be prepared in situ during the final isolation and purification of the compounds described or separately by reacting a free base function with a suitable organic acid. Representative acid addition salts include, but are not limited to, acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsufonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2- hydroxyethansulfonate(isethionate), lactate, maleate, methanesulfonate, nicotinate, 2- naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenyl propionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, phosphate, glutamate, bicarbonate, p-toluenesulfonate and undecanoate. Also, the basic nitrogen-containing groups may be quaternized with such agents as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl and diamyl sulfates; long chain halides, such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides; arylalkyl halides, such as benzyl and phenethyl bromides, and others. Water or oil-soluble or dispersible products are thereby obtained. Examples of acids which may be employed to form pharmaceutically acceptable acid addition salts include such inorganic acids as hydrochloric acid, hydrobromic acid, sulphuric acid and phosphoric acid and such organic acids as oxalic acid, maleic acid, succinic acid and citric acid. Basic addition salts may be prepared in situ during the final isolation and purification of compounds described within the invention by reacting a carboxylic acid-containing moiety with a suitable base such as the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation or with ammonia or an organic primary, secondary or tertiary amine. Pharmaceutically acceptable salts include, but are not limited to, cations based on alkali metals or alkaline earth metals such as lithium, sodium, potassium, calcium, magnesium and aluminum salts and the like and nontoxic quaternary ammonia and amine cations including ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine and the like. Other representative organic amines useful for the formation of base addition salts include ethylenediamine, ethanolamine, diethanolamine, piperidine, piperazine and the like. Pharmaceutically acceptable salts may be also obtained using standard procedures well known in the art, for example by reacting with a sufficiently basic compound such as an amine with a suitable acid affording a physiologically acceptable anion. Alkali metal (for example, sodium, potassium or lithium) or alkaline earth metal (for example calcium or magnesium) salts of carboxylic acids may also be made.

According to some embodiments, the described invention provides a kit comprising a composition and a packaging material. According to some embodiments, the kit further comprises a means for administering the composition. According to some embodiments, the composition comprises at least one ROCK compound. According to some embodiments, at least one ROCK inhibitor compound is telmisartan. According to some embodiments, the packaging material is an instruction. According to some embodiments, the means for delivering the composition comprises a syringe comprising the composition. According to some embodiments, the composition of the kit further comprises a pharmaceutically acceptable excipient.

Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limit of that range and any other stated or intervening value in that stated range is encompassed within the invention. The upper and lower limits of these smaller ranges which can independently be included in the smaller ranges is also encompassed within the invention, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either both of those included limits are also included in the invention.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the described invention, the preferred methods and materials are now described. All publications mentioned herein are incorporated herein by reference to disclose and described the methods and/or materials in connection with which the publications are cited.

Components of the formulation:

Drug substance

Chemical Name and structure

Telmisartan:

Chemical Name: 4'-[[4-methyl-6-(1 -methyl-1 H-benzimidazol-2-yl)-2-propyl-1 H- benzimidazol-1-yl]methyl]biphenyl-2-carboxylic acid.

Molecular Weight: 514.63gm/mol

Molecular Formula: C33H3oN₄C>2

Chlorthalidone:

Chemical name: 2-chloro-5-(1-hydroxy-3-oxo-2H-isoindol-1 yl) benzenesulfonamide. Molecular Weight: 338.762 g/mol

Molecular Formula: C14H11CIN2O4S Cilnidpine:

Chemical name: 3-0-(2-methoxyethyl) 5-0-[(E)-3-phenylprop-2-enyl] 2,6- dimethyl-4- (3-nitrophenyl)-1 ,4-dihydropyridine-3,5- dicarboxylate.

(a) Physicochemical properties (b.1) Solubility:

Telmisartan: A white or yellowish crystalline powder, practically insoluble in water <0.1 mg/ml_ (<0.01 %w/v)

Chlorthalidone: White to yellowish-white crystalline powder, Chlorthalidone is practically insoluble in water, in ether and in chloroform; soluble in methanol;

slightly soluble in alcohol.

Cilnidipine: Light yellowish powder, practically insoluble in water <1 mg/mL.

(b.2) Stability:

The product should be protected from light and moisture.

Formulation development

Design of experiments (DOE)

The tablet consists of two layers, the first layer contains chlorthalidone plus cilnidpine and their excipients and the second layer composed of Telmisartan and its excipients (FIGURE 1 ). A bilayer system has been used due to incompatability of Telmisartan excipients which is (Alkaline microenvironment) with two susciptable other API’s, Cilindipine and Chlorthalidone bilayer tablet is designed to compress two granular separate mixture on a special double layer rotary tableting machine.

In order to determine what experiments are needed to define the design space of the manufacturing process, the critical quality attributes (CQA) are specified as follows: Finished product specification and critical quality attributes (CQA)

The CQA were determined as follow:

1. Critical parameters related to finished dosage form of the combination product:

a. Design of bilayer tablets that contains Telmisartan in one layer, and

Chlorthalidone with Cilnidipine in the second layer.

b. All triple active ingredients as an immediate release formulation.

c. Each drug in the final dosage form shall have similar dissolution profile to the individual reference product.

2. Critical parameters related to Chlorthalidone/ Cilnidipine layer:

a. To obtain the desired dissolution profile, co- dispersion of Cilnidipine and Chlorthalidone with povidone co-polymer in methanol was found to be essential. Surprisingly, dispersion of each drug alone doesn’t reach the target dissolution profile. This step is believed to be innovative and novel for the two drug combination.

b. Wet granulation technique to disperse two active ingredients in powder mixture.

c. Inclusion of surfactant in powder mixture to enhance wetting and

dissolution.

d. Use of super disintegration such as Crospovidone to obtain immediate release profile.

3. Critical parameters related to Telmisartan layer:

a. Active ingredient is dissolved in queues alkaline mixture (NaOH

+Megluminee) with binder (povidone K30) in order to make this layer alkaline enough to affect dissolution of active ingredient. b. Wet granulation of above solution in powder mixture containing water soluble fillers (Mannitol and Sorbitol) in addition to Microcrystalline cellulose to absorb liquid binder and entrap alkalinity with active ingredients.

c. Due to high content of soluble material this layer is slowly dissolving to affect dissolution of immediate release formulation. Parameters related to operating conditions:

a. Due to hygroscopicity of Telmisartan layer operating condition should be under dry condition (RH < 40 %).

b. Due to sensitivity of Cilnidipine, all process was done in dark conditions. Parameters related analytical conditions:

a. Due to light sensitivity of Cilnidipine, all analytical activities are under conditions.

b. Dissolution conditions are polysorbate 80 (1 %) surfactant based system to enhance dissolution of Cilnidipine to enhance dissolution of Cilnidipine to simulate in vivo conditions. Parameters related to primary packaging material:

a. To protect product against humidity and light, the following primary

packaging materials are recommended:

• Alu/Alu blister

• HDPE opaque containers with desiccant.

• Amber glass containers with desiccant.

Initial risk assessment of Tel isartan, Chlorthalidone & Cilnidipine coming from process/formula factors are listed in TABLE 1.

The critical process and formulation parameters were determined based on the impact on CQA, using risk analysis plan outlines in TABLE 2.

According to the above risk assessment matrix, the following were recognized as critical to the manufacturing process:

1. API particle size.

2. Preparing solid dispersion.

3. Massing (granulation) time.

4. Milling.

5. Compression force (or hardness).

Selection of Active pharmaceutical ingredient (API)

The selection of source of active ingredient was based on the followings:

Availability of DMF in CTD format.

Certificate of analysis with all required tests and specifications

Impurity profile that complies with ICH guideline.

Particle size distribution that meets the requirements.

The source that found to meet the above criteria:

1. Telmisartan: Alembic Pharmaceutical Ltd.

2. Chlorethalidone: MENADIONA

3. Cilnidipine: UNIQUE Chemicals (A Division of J.B Chemicals &

Pharmaceuticals Ltd.)

Selection of Excipient

The selection of excipients was carried out to produce film coated tablets. Published data on the qualitative composition of this product, experience in tablet formulation and the possible manufacturing process with the available machinery have been used as a basis.

The following TABLE 3 shows the excipients used in the Telmisartan, Chlorthalidone & Cilnidipine film coated tablet formulation study.

Compatibility of the drug substance with Excipients The compatibility of the excipients used in this formulation was evaluated physically and chemically. Only compatible excipients were used in this formulation

Several excipients covering all intended pharmaceutical applications were evaluated and tested. The following table summarizes all excipients used in this study and the compatibility status (TABLE 4). Samples were prepared and evaluated using HPLC stability indicating method.

List of experiments/Examples

EXAMPLE 1 : Evaluation of compatibility of Cilnidipine and Chlorothalidone when used intra and extra granular

EXAMPLE 2: Evaluation of wet granulation process of Telmisartan and bilayer tableting process

EXAMPLE 3: Evaluation of wet granulation process of Telmisartan and bilayer tableting process

EXAMPLE 4: Telmisartan solubility improvement. Effect of additives like NaOH, PVP- K30 and Meglumine.

EXAMPLE 5: Effect of Meglumine on Telmisartan solubility and dissolution.

EXAMPLE 6: Telmisartan drug release improvement

EXAMPLE 7: To improve dissolution release Chlorthalidone by adding Polysorbate 20 to the dispersion of Chlorthalidone/cilnidipine in the IPA, and by replacing of prosolv 90 with lactose monohydrate

EXAMPLE 8: To improve dissolution release of Chlorthalidone by using PVP-K-12 instead of PVP K-30 and using Methanol instead of isopropanol alcohol.

EXAMPLE 9: To evaluate dissolution release of all active for Bilayer tablet using 0.25% SLS dissolution medium

EXAMPLE 10: Reducing of tablet weight to using same formulation for immediate release bilayer tablet and for DR tablet in capsule formula.

Example No.1

Evaluation of compatibility of Cilnidipine and Chlorothalidone when used intra and extra granular. TABLE 5A shows the composition of the formulation. Tablets are filled in HDPE jars and stored at 55°C for 2 months to study the compatibility of Cilnidipine and Chlorthalidone by HPLC (STP# ). Results showed Cilnidipine is compatible with Chlorothalidone and can be used in one tablet/layer where one of the drug is extra granular (TABLE 5B).

Example No.2:

Evaluation of wet granulation process of Telmisartan and bilayer tableting process To evaluate wet granulation process of Telmisartan and bilayer tableting process. Composition of the tablet is in Table 6A.

Procedure: Disperse Cilnidipine and PVP-k30 in IPA then granulate with prosolv 90 and crospvidone and SLS. and adding of Chlortalidone as extra granulation. Afterward, dissolve sodium hydroxide in purified water, then granulate with Telmisartan, Meglumine, pvp-k30 and sorbitol then compression of bilayer.

Dissolution results are not within acceptable limits (Table 6 B); Need to improve the solubility and drug release for all active ingredients.

Example No.3:

Wet granulation process improvement of Telmisartan using hydro alcoholic granulation solution. Effect of Mannitol and MCC. Composition of tablet formulation in TABLE 7A.

Method: Disperse Cilnidipine and PVP-k30 in IPA then granulate with prosolv 90 and crospvidone and SLS and adding of Chlortalidone as extra granulation. Afterward dissolve sodium hydroxide in small quantity of purified water the mix with isopropanol, then granulate with Telmisartan, Meglumine, pvp-k30 and sorbitol. Finally compression of bilayer tablet. Testing of dissolution release for the three active using the following parameters: Medium: buffer pH 6.8, 75 RPM, volume: 900.

Dissolution results (TABLE 7B) are not within acceptable limits; Need to improve the solubility and drug release for all active ingredients.

Example No.4:

Telmisartan solubility improvement. Effect of additives like NaOH, PVP-K30 and Meglumine. Composition TABLE 8A.

Disperse Cilnidipine and PVP-k30 in IPA then granulate with prosolv 90 and

crospvidone and SLS. and adding of Chlorthalidone as extra granulation. Dissolving of NaOH, Telmisartan, PVP-K30 and Meglumine in hydro alcoholic solution then granulate with Mannitol fine, Mannitol SD and Crospovidone. Adding Compresol SM extra granules. Finally compression of bilayer tablet.

Testing of dissolution release for the three active using the following parameters:

Medium: buffer pH 6.8, 75 RPM, volume: 900.

Dissolution results for Telmisartan and Cilnidipine has been improved (TABLE 8B) and Chlorthalidone dissolution still needs further improvement.

Example No.5: Effect of Meglumine on Telmisartan solubility and dissolution. Composition is shown in TABLE 9A.

METHOD: Disperse Cilnidipine and PVP-k30 in IPA then granulate with prosolv 90 and crospvidone and SLS. and adding of Chlorthalidone as extra granulation. Afterward dissolving of NaOH, Telmisartan, PVP-K30 and Meglumine in hydro alcoholic solution then granulate with Mannitol fine, Mannitol SD and Crospovidone. Adding compresol SM extra granules. Finally compression of bilayer tablet. Testing of dissolution release for the three active using the following parameters: Medium: buffer pH 6.8, 75 RPM, volume: 900

Dissolution results (TABLE 9B) are not within acceptable limits; Need to improve the solubility and drug release for Telmisartan and Chlorthalidone

Example No.6:

To improve release of Telmisartan and to evaluate new process for Chlorthalidone/Cilnidipine layer by dispersing Chlorthalidone in the IPA in addition to Cilnidipine and PVP-k30 and increasing amount of SLS. Composition is shown in TABLE 10A.

METHOD: Disperse Cilnidipine; Chlorthalidone and PVP-k30 in IPA then granulate with prosolv 90, crospvidone and SLS. Afterward dissolving of NaOH, Telmisartan, PVP-K30 and Meglumine in hydro alcoholic solution then granulate with Mannitol fine, Mannitol SD and crospovidone. Adding Compresol SM extra granules. Finally compression of bilayer tablet. Testing of dissolution release for the three active using the following parameters: Medium: water, 75 RPM, volume: 900.

Dissolution results of cilnidipine (TABLE 10B) are within acceptable limits, however, Chlorthalidone dissolution still needs further improvement.

Example No.7:

To improve dissolution release Chlorthalidone by adding polysorbate 20 to the dispersion of Chlorthalidone/Cilnidipine in the IPA, and by replacing of prosolv 90 with lactose monohydrate. Composition is shown in TABLE 11 A.

METHOD: Disperse Cilnidipine, Chlorthalidone, polysorbate 20 and PVP-k30 in IPA then granulate with lactose mesh 200, crospvidone and SLS. Afterward, dissolving of NaOH, Telmisartan, PVP-K30 and Meglumine in hydro alcoholic solution then granulate with Mannitol fine, Mannitol SD and Crospovidone. Adding Compresol SM extra granules. Finally compression of bilayer tablet.

Testing of dissolution release for the three active using the following parameters:

Medium: buffer pH 6.8, 75 RPM, volume: 900

Dissolution results of Chlorthalidone (TABLE 11 B) has been improved, but needs further optimization and similarity.

Example No.8

To improve dissolution release of Chlorthalidone by using PVP-k-12 instead of PVP k-30 and using Methanol instead of isopropanol alcohol.

METHODS: Disperse Cilnidipine, Chlorthalidone and PVP-k12 in methanol then granulate with lactose mesh 200 and Crospovidone and SLS. Then compression of single tablet Chlorthalidone /Cilnidipine. Testing of dissolution release for the three active using the following parameters:

Medium: water, 75 RPM, volume: 900

TABLE 12A shows the composition of the formulation. TABLE 12B shows Dissolution results and similarity of Chlorthalidone has been improved and similarity with reference product matched. Experiment No.9

To evaluate dissolution release of all active for Bilayer tablet using 0.25% SLS dissolution medium.

METHODS: Disperse Cilnidipine, Chlorthalidone, and PVP-k12 in methanol then granulate with lactose mesh 200, crospvidone and SLS. Afterward, dissolving in hydro alcoholic solution of NaOH, Telmisartan, PVP-K12 and Meglumine then granulate with Mannitol fine, Mannitol SD and Crospovidone. Adding compresol SM extra granules . Finally compression of bilayer tablet. TABLE 13A shows the composition of the tablet. Testing of dissolution release for the three active using the following parameters: Medium: 0.25% SLS, 75 RPM, volume: 900.

Dissolution results of Cilnidipine, Chlorthalidone and Telmisartan has been improved (shown in TABLE 13B (Chlorthalidone), TABLE 13C (Telmisartan), FIGURE 2 (Chlorthalidone), FIGURE 3 (Telmisartan), FIGURE 4 (Cilnidipine), and similarity obtained. Experiment 9 resembles the preferred formulation. The in vitro dissolution rate of the three drugs along with the corresponding pharmacokinetic behaviour believed to be responsible for targeting the circadian rhythm in resistant hypertensive patient and bringing back to normal.

Experiment No.10: Effect of tablet weight using same formulation for immediate release bilayer tablet and for DR tablet in capsule formula. TABLE 14A shows the composition of the tablet

Preparing each active in separate mixture, compress each active in single tablet.

Testing of dissolution release for each single tablet using the following parameters: Medium: 0.25% SLS, 75 RPM, volume: 900.

Dissolution results of all active have declined for all active. Dissolution results of Cilnidipine, Chlorthalidone and Telmisartan has been improved (shown in TABLE 14B (Cilnidipine), TABLE 14C (Telmisartan), TABLE 14D (Chlorthalidone),

Effect of tablet weight using same formulation for immediate release bilayer tablet and for DR tablet in capsule formula (Cilindipine) is shown in FIGURE 5. Effect of tablet weight using same formulation for immediate release bilayer tablet and for DR tablet in capsule formula (Telmisartan) is shown in FIGURE 6. Effect of tablet weight using same formulation for immediate release bilayer tablet and for DR tablet in capsule formula (Chlorthalidone) is shown in FIGURE 7.

Selection of Excipient

Table 15 shows the rational behind excipients used in the tablet formulation.

Overages

No overage will be used for Cilnidipine, Chlorthalidone and Telmisartan in the formulation.

Manufacturing process development Cilnidipine +Chlorthalidone Layer:

Wet granulation technique with suitable excipients to give immediate release formulation with good dissolution profile.

Telmisartan Layer:

Wet granulation technique with suitable basic excipients to give immediate release formulation with good dissolution profile.

Process flow chart is shown in FIGURE 8.

Manufacturing process is shown in FIGURE 9A and FIGURE 9B.

Container Closure System

Selection of Primary packaging material:

Due to sensitivity of Triple therapy to light and moisture, the following container closure systems are required to be studied:

1- Alu/Alu blister.

2- White opaque HDPE with white opaque polypropylene closure and desiccant.

3- Amber glass bottle with white opaque polypropylene closure and desiccant.

Stability studies, both long term (30 °C ± 2°C) and accelerated studies (40 °C ± 2°C), confirmed the reliability of using this type of containers as a primary packaging material.

The packaging material will undergo regular quality control tests in compliance with Good Manufacturing Practice (GMP) standards.

Microbiological Attributes

Tests for microbiological contamination have been performed on the product. In compliance with the USP, a specification for aerobic bacteria per g; fungi per g and E.Coli per g has been included.

Compatibility

Compatability will be concluded through the finished product stability study in the final package.

It must be noted that as used herein and in the appended claims, the singular forms "a", "and", and "the" include plural references unless the context clearly dictates otherwise. All technical and scientific terms used herein have the same meaning. TABLE 1 : Initial risk assessment of Telmisartan, Chlorthalidone & Cilnidipine

The below table lists the potential risks coming from process/formula factors:

TABLE 2: The critical process and formulation parameters were determined

Table (3): Telmisartan, Chlorthalidone & Cilnidipine film coated Tablet used excipients

TABLE 4: table summarizes all excipients used in this study and the compatibility status. Samples were prepared and evaluated using HPLC stability indicating method.

TABLE 5A: Evaluation of compatibility of Cilnidipine and Chlorothalidone when used intra and extra granular

Composition

TABLE 5B: Results showing Cilnidipine is compatible with Chlorothalidone and can be used in one tablet/layer where one of the drug is extra granular

TABLE 6A: To evaluate wet granulation process of Telmisartan and bilayer tableting process. Composition is below

TABLE 6B: Dissolution results are not within acceptable limits; Need to improve the solubility and drug release for all active ingredients.

TABLE 7A: Wet granulation process improvement of Telmisartan using hydro alcoholic granulation solution. Effect of Mannitol and MCC. Composition of tablet formulation:

TABLE 7B: Dissolution results are not within acceptable limits for tablet formulation in table 7A; Need to improve the solubility and drug release for all active ingredients.

TABLE 8A: Telmisartan solubility improvement. Effect of additives like NaOH, PVP- K30 and Meglumine. Composition of formulation:

TABLE 8B: Dissolution results for Telmisartan and Cilnidipine in formulation in Table 8A has been improved and Chlorthalidone dissolution still needs further improvement.

TABLE 9A: Effect of Meglumine on Telmisartan solubility and dissolution.

TABLE 9B: Dissolution results for composition in table 9A are not within acceptable limits; Need to improve the solubility and drug release for Telmisartan and Chlorthalidone

TABLE 10A: To improve release of Telmisartan and to evaluate new process for Chlorthalidone/Cilnidipine layer by dispersing Chlorthalidone in the IPA in addition to Cilnidipine and PVP-k30 and increasing amount of SLS. Composition below for example 6:

TABLE 10B: Dissolution results of cilnidipine for formulation shown in table 10A are within acceptable limits, however, Chlorthalidone dissolution still needs further improvement

TABLE 11 A: To improve dissolution release Chlorthalidone by adding polysorbate 2 dispersion of Chlorthalidone/Cilnidipine in the IPA, and by replacing of prosolv 90 witl monohydrate. Composition is shown below for example 7.

TABLE 11 B: Dissolution results of Chlorthalidone in formulation table 11A has been improved, but needs further optimization and similarity.

TABLE 12A shows the composition of the formulation in Example 8:

TABLE 12B shows Dissolution results and similarity of Chlorthalidone has been improved and similarity with reference product matched.

TABLE 13A shows the composition of the tablet in Example 9.

TABLE 13B: Dissolution results of Chlorthalidone in the formulation shown in TABLE 13A.

TABLE 13C: Dissolution results of Telmisartan in the formulation shown in TABLE 13A

TABLE 14A: shows the composition of the tablet in Example 10.

TABLE 14B Dissolution results of Cilnidipine. Results related to Example 10 study.

TABLE 14C Dissolution results of Telmisartan. Results related to Example 10 study.

TABLE 14D Dissolution results of Chlorothalidone. Results related to Example 10 study.

Table 15 shows the rational behind excipients used in the tablet formulation.

Claims

1 . A pharmaceutical composition for lowering blood pressure and comprising effective amounts of cilnidipine, telmisartan and Chlorthalidone.

2. The pharmaceutical composition for lowering blood pressure according to claim 1 , consisting essentially of telmisartan, cilnidipine and Chlorthalidone as active ingredients.

3. The pharmaceutical composition for lowering blood pressure according to claim 1 , which comprises 5 to 80 mg of telmisartan and 1.25 to 20 mg of cilnidipine.

4. The pharmaceutical composition for lowering blood pressure according to claim 1 , which comprises 10 to 80 mg of telmisartan and 1.25 to 20 mg of cilnidipine and 10 to 25 mg Chlorthalidone.

5. The pharmaceutical composition for lowering blood pressure according to claim 1 , which comprises telmisartan, Cilnidipine and Cilnidipine in a weight ratio of . 16:8:10 to 16:2:5

6. The pharmaceutical composition for lowering blood pressure according to claim 1 , which comprises 80 mg of telmisartan, 5 mg of cilnidipine and 12.5 mg Chlorthalidone.

7. The pharmaceutical composition for lowering blood pressure according to claim 1 , which comprises 40 mg of telmisartan, 10 mg of cilnidipine and 12.5 mg Chlorthalidone.

8. The pharmaceutical composition for lowering blood pressure according to claim 1 , which comprises 20 to 80 mg of telmisartan, 5- to 20 mg of cilnidipine and 12.5 to 25 mg Chlorthalidone.

9. The pharmaceutical composition for lowering blood pressure according to claim

10. The pharmaceutical composition for lowering blood pressure according to claim 1 , which is formulated in oral dosage from.

1 1. The pharmaceutical composition for lowering blood pressure comprising effective amounts of Telmisartan, Cilnidipine and Chlorthalidone and act by targeting the circadian rhythm of hypertension, which is used for treatment of hypertension, heart failure, coronary heart disease, ischemic heart disease, ischemic peripheral vascular disease, hypertensive renal failure, stroke or atherosclerosis, resistant hypertension.

12. The pharmaceutical composition for lowering blood pressure according to claim 11 , which comprises 5 to 80 mg of telmisartan and 1.25 to 20 mg of cilnidipine.

13. The pharmaceutical composition for lowering blood pressure according to claim 11 , which comprises 10 to 80 mg of telmisartan and 1.25 to 20 mg of cilnidipine and 10 to 25 mg Chlorthalidone.

14. The pharmaceutical composition for lowering blood pressure according to claim 11 , which comprises telmisartan, Cilnidipine and Cilnidipine in a weight ratio of . 16:8:10 to 16:2:5

15. The pharmaceutical composition for lowering blood pressure according to claim 11 , which comprises 80 mg of telmisartan, 5 mg of cilnidipine and 12.5 mg Chlorthalidone.

16. The pharmaceutical composition for lowering blood pressure according to claim 11 , which comprises 40 mg of telmisartan, 10 mg of cilnidipine and 12.5 mg Chlorthalidone.

17. The pharmaceutical composition for lowering blood pressure according to claim 11 , which comprises 20 to 80 mg of telmisartan, 5- to 20 mg of cilnidipine and 12.5 to 25 mg Chlorthalidone.

18. The pharmaceutical composition for lowering blood pressure according to claim 11 , which is formulated in oral dosage from.

19. The pharmaceutical composition according to claim 11 which is made using bi-layer tablet.

20. The pharmaceutical composition according to claim 11 , where Telmisartan formulated in one layer and Cilnidipine and Chlorthalidone are together in a second layer.

21. The pharmaceutical composition according to claim 12, where Cilnidipine and Chlorthalidone are prepared by co-dispersion of Cilnidipine and Chlorthalidone together in the same.