Irbesartan is a strong and long effective non-peptide tetrazole derivative and an angiotensin II type 1 receptor (AT1) antagonist. Its chemical composition is as follows: 2-butyl-3-[[2'-(lH-tetrazol-5-yl) [1, 1'-biphenyl]-4-yl] methyl] 1, 3-diazaspiro [4,4] non- 1-en-4-one. It is used alone or with other antihypertensive agents to treat high blood pressure. Irbesartan is clinically used alone as once-daily doses of 75 mg, 150 mg or 300 mg or combined with other antihypertensive agents to treat hypertension.
Irbesartan is a white crystalline powder that is slightly soluble in alcohol and methylene chloride and insoluble in water. The low aqueous solubility of irbesartan also presents a challenge, since, to keep the tablet mass small, only limited amounts of excipients may be added to facilitate wetting, disintegration, and ultimately, rapid and complete drug release The starting, without delay, of the antihypertensive property has a vital importance for the therapeutic activity of the formulation. For that purpose, the formulation's dissolution properties are determinant.
Irbesartan is a fluffy material, with relatively low bulk and tap densities. These properties make it difficult to formulate a large amount of the drug into a small tablet with uniformity of weight, hardness, and other desirable tablet properties.
In addition, irbesartan has certain undesirable flow characteristics It is sticky and can adhere to surfaces such as tablet punch faces and dies, causing problems in tableting, especially on a high speed tablet press.
Thus, there is a need in the art for pharmaceutical compositions containing irbesartan, alone or in combination with a diuretic, which have good properties for tablet formation, and yet which contain a minimal mass of excipients so that small, easily swallowed tablets which enhance patient acceptance and compliance with a high content of active agent may be prepared, and provide tablets with excellent wetting, disintegration, and ultimately, rapid and complete drug release properties.
In order to reach a quick reaction, the developed antihypertensive drugs have been formulated so to reach minimum 80% of dissolution at 15 minutes after dosing and minimum 90% of dissolution at 30 minutes after dosing. based on the total weight of irbesartan contained in the tablet, which dissolves within 30 minutes under the following conditions: using a tablet having a total weight of from 150 to 600 mg and a USP Apparatus 2, placing the tablet in 1000 mL of 0.1 N hydrochloric acid at 37° C., with a paddle speed of 50 rpm, and measuring the amount of irbesartan dissolved (especially, using UV at 244 nm or, when hydrochlorothiazide is also present, using HPLC, wavelength 272 nm) at 30 minutes. (If desired, the progress of dissolution may also be monitored at various time points.)
The diluent/filler employed in a composition of the present invention may be one or more compounds which are capable of providing bulk to obtain a desired tablet mass. It is desirable to employ the diluent in an amount at the lower end of the weight range for the diluent. Preferred diluents are Lactose, pregelatinized starch, avicel 102 (cellulose or cellulose derivatives such as microcrystalline cellulose).
The binder employed in a composition of the present invention may be one or more compounds which are capable of facilitating granulation of the irbesartan and/or diuretic into larger and free-flowing particles. Preferred binders hydroxypropyl methylcellulose or pregelatinized starch.
The disintegrant employed in a composition of the present invention may be one or more compounds which are capable of facilitating the break up of a tablet prepared from the composition when placed in contact with an aqueous medium. Preferred disintegrants are microcrystalline cellulose, croscarmellose sodium (cross-linked polymer of carboxymethylcellulose sodium), crospovidone (cross-linked homopolymer of N-vinyl-2-pyrrolidinone, i.e., cross-linked 1-ethenyl-2-pyrrolidinone) pregelatinized starch (most preferably employed in the range of 5-10% by weight), sodium starch glycolate or Ac-Di-Sol.
The glidant/antiadherent employed in a composition of the present invention may be one or more compounds which are capable of reducing the stickiness of the formulation, for example, preventing adherence to metal surfaces. Preferred antiadherents are silicon dioxide(aerosol) or talc.
The lubricant employed in a composition of the present invention may be one or more compounds which are capable of preventing tableting problems, such as those relating to the release of a tablet prepared from the composition from the apparatus on which it is formed, for example, preventing adherence to the face of the upper punch (picking) or lower punch (sticking) of a tableting apparatus. Preferred lubricants are calcium stearate, magnesium stearate, or talc.
The surfactan" employed in a composition of the present invention may be one or more compounds which are capable of improving the wetting of the tablets and/or enhancing dissolution. Preferred surfactants are sodium lauryl sulfate, and poly(oxyethylene),poly(oxypropylene) block co-polymers such as poloxamers, especially poloxamer 188.
In this formulation, the following ingredients are used: - spray dried lactose, pre-gelatinized starch as filling material and/or binding agent – Microcrystalline Cellulose 102 as filling material – Croscarmellose Sodium as disintegrant - Poloxamer 188 as surfactant – Silidon Dioxide Colloidal as glidant – Talc and Magnesium stearate as lubricant This formulation was prepared according to the wet granulation method.
Given that irbesartan is not soluble in water, Poloxamer 188 that is a non-ionic surfactant is used in our formulation in order to augment the solubility. The proportion of sodium lauryl sulphate used in the formulation represents3% of the tablet's weight. During the development of the formulation, granulation was done with the water and alcohol solutions of Poloxamer 188. However when instead of water alcohol was used for the granulation, it appeared that irbesartan had a soluble property in alcohol and that thanks to this property better dissolution results were obtained.
According to that, during the granulation with the alcoholic Poloxamer solution, a part of the irbesartan was dissolved and this dissolved part recrystallized with the Poloxamer while drying. For that reason, the granulation made with alcohol gives better dissolution values than the one made with water.
The filling materials used in our formulation are spray dried lactose, Microcrystalline Cellulose 102 and pre-gelatinized starch.
When formulations of irbesartan were prepared by using lactose monohydrate, the dissolution results being not at the expected level, spray dried lactose, were used in replacement to prepare formulations because they are constituted of smaller particle size.
Our formulations show that the spray dried lactose are more appropriate excipients. Owing to the small size of its particles, spray dried lactose offers a bigger specific surface area. For that purpose, the active ingredient granulized with spray dried lactose gave the desired dissolution specificities thanks to the wide surface area that resulted after the disintegration of the tablets or capsules prepared according to this technique. The proportion of spray dried lactose used in the formulation represents 30% of the tablet's weight.
Microcrystalline Cellulose 102 is an appropriate excipient for the direct compression. The disintegrating properties of this ingredient were also used in our formulation. This is why, after the preparation of the granules, they were mixed with Microcrystalline Cellulose 102 and then the tablets were compressed.
The pre-gelatinized starch is used for the tablets prepared with the wet granulation method because of its poor fluidity properties. In the formulation, we also took advantage of the binding characteristics of the pre-gelatinized starch.
In order to ensure a rapid disintegration, the disintegrant added to the formulation is the super disintegrant Crosscarmellose Sodium.
Silicon Dioxide Colloidal was added to the formulation to reduce the static electricity generated among the powder particles and by doing so it is aimed to improve the fluidity features. The lubricant used in the formulation is combination between talc and magnesium stearate. Thus, the compression process can be done without the tablets adhering to the tablet punch. Differently from the known formulations of irbesartan, the present innovation contains spray dried lactose. Besides, in the developed formulation, the granulation was operated with alcohol instead of water and this granulation process leads to more suitable dissolution related values. Reaching higher dissolution values and a quicker dissolution process are two wanted features of the antihypertensive agents of the pharmaceutical formulations. In those conditions, the antihypertensive activity is expected to start earlier and to work more efficiently. Reaching higher dissolution values and a quicker dissolution process are realized through the use of Cellactose 80 and/or spray dried lactose and through the application of the granulation process with alcohol.
Ingredient Component (% w/w)
Irbesartan Active Drug 50.0 %
Spray Dried Lactose Diluent 20.0 %
Microcrystalline Cellulose 102 Diluent, disintegrant 9.0 %
Pregelatinized Starch Diluent, Binder 8.0 %
Crosscarmellose Sodium Disintegrant 1.5 %
Poloxamer 188 Surfactan 3.0 %
Ethylalcohol-water Wetting agent 3:1
Microcrystalline Cellulose 102 Diluent, disintegrant 5.0 %
Crosscarmellose Sodium Disintegrant 1.5 %
Talc Antiadherent 1.0 %
Silicon Dioxide Colloidal Glidant 0.5 %
Magnesium Stearate Lubricant 0.5 %