FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patent Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
TITLE OF THE INVENTION
"AN IMPROVED SUSTAINED RELEASE FORMULATION OF
METOLAZONE"
We, BA Research India Limited, of BA Research House, Opposite "Pushparaj Towers", Nr. Judges Bunglows, Bodakdev, Ahmedabad-380054, Gujarat, India.
The following specification particularly describes the nature of the invention and the manner in which it is performed:

Field of the Invention
The present invention relates to an improved sustained release formulation of the drug metolazone, and to a method for preparing such formulations. Background of the Invention-
Metolazone,7-chloro-l,2,3,4-tetrahydro-2-methyl-3-(2-methylphenyl)-4-oxo-6-quinazolin esulfonamide, is a potent antihypertensive and diuretic drug. Metolazone is a diuretic structurally related to quinethazone but has a greater potency, on a weight basis, than either quinethazone or hydrochlorothiazide. Metolazone is commonly available in oral dosage forms. Particularly in critical care situations such as for treatment of refractory edema or renal failure, a more desirable form of the drug is as an injectable solution. Aqueous solutions are preferred for intravenous administration, however, metolazone has very low solubility in water (about 0.02 mg/ml).
One approach to produce aqueous solutions of metolazone has been to increase the pH of the solution by the addition of, for example, alkali hydroxides. An aqueous solution having a pH of about 11 is sufficient to solubilize metolazone. However, such a high pH is undesirable for use in parenteral administration due to pain and irritation at the site of injection and possible precipitation of the metolazone. Moreover, metolazone is chemically unstable at this high pH. An example of using a high pH to solubilize metolazone is found in the work of Vasant Ranade (U.S. Pat. Nos. 5,633,240, 5,684,009, and 5,814,623). The highest concentration of metolazone achieved without precipitation was 2 mg/ml, and even this concentration usually resulted in precipitation. See Tables 1 and 2 of any of the Ranade patents. The preferred solutions in the Ranade patents contain about 1 mg/ml of metolazone. See U.S. Pat. No. 5,633,240 at column 2, lines 51 to 53.
Various other solutions to the problem of low metolazone solubility have been suggested in the art. Combining metolazone with other drugs to increase its effectiveness has been suggested. The formation of aqueous solutions containing various solvents and metolazone has also been reported. For example, aqueous metolazone solutions containing propylene glycol and ethyl alcohol have been produced in, for example, U.S. Patent. No. 5,124,152 (Biringer et al.). This patent exemplifies aqueous metolazone solutions having concentrations up to 4.25 mg/ml, and these solutions include some having a cosolvent of propylene glycol and ethyl alcohol. The '152 patent claims an aqueous metolazone solution having a concentration from 0.1 to 8 mg/ml of metolazone. The apparent equilibrium solubility limit of metolazone in an aqueous solution of 65% w/v propylene glycol, 15% w/v ethyl alcohol is approximately 8 mg/ml. See below. FIG. 1 of the '152 patent demonstrates that certain solutions can be formed using metolazone, ethyl alcohol, and propylene glycol.

These solutions were formed by mixing the metolazone with the propylene glycol/ethyl alcohol mixture and then adding water. No heating was used. The metolazone in the solution shown in FIG. 1 of the '152 patent was above its apparent equilibrium solubility limit below about 2 mg/ml.
With some metolazone solutions containing organic solvents, there can be problems of irritation or precipitation of the drug at the site of injection. Thus, it is desirable to administer as low a total volume of the injectable solution as possible in order to minimize the side effects due to non-aqueous solvents. It is also desirable to prevent precipitation upon intravenous injection as it can result in reduced bioavailability of the drug, pain upon injection, or phlebitis.
Precipitation at the site of drug injection is related to the solubility of the drug in biological fluids. The rate of administration of a solution of a drug determines the degree of dilution in biological fluids and whether the solubility of the drug in the mixture of fluids will be exceeded. Normally one would expect that if the concentration of the drug at the site of injection exceeds the solubility of the drug in the biological fluid, precipitation would occur. Currently, the sustained release formufation of metolazone which we manufacture consists of small wax-coated granules of the drug encapsulated in a soft gelatin capsule. The granules themselves are formed by a conventional granulation technique using gelatin as a binder to hold the particles of drug powder together, and then the coating of wax, which serves to control the in vivo rate of release of the drug by diffusion is applied by spraying. However, as the granules themselves are inevitably of irregular shape, the applied wax coating tends to be of uneven thickness, which of course in turn affects the drug-release properties of the coating. Now the desired sustained drug release profile is obtained by mixing together different batches with different thicknesses of wax coating, but because of the difficulty referred to of ensuring evenly coated granules it is actually, in practice, difficult to ensure that the desired release profile is consistently obtained.
The need for sustained release formulation of metolazone which can be more efficiently and more consistently produced is apparent.
Therefore the present invention provides the new sustained release formulation of metolazone where metolazone itself acts as its own binder to enable the desired high drug loading to be achieved. We postulate that a small proportion of the metolazone dissolves during the wet blending step to form "liquid bridges" between the particles. On drying, removal of the water will leave interparticulate bonds within the structure of the pellets, whereby the pellets retain their coherency.

Summary of the Invention
In one embodiment the present invention provides a new sustained release formulation of metolazone which comprises substantially spherical, essentially binder-free pellets containing at least 25% by weight of metolazone, said pellet being individually coated with a release-controlling membrane.
In yet another embodiment the invention provides a process for manufacturing of the sustained release formulation of metolazone. Brief Description of the Accompanying Drawing
Figure 1 depicts the mean metolazone plasma concentration plotted against the time for study in elderly patients.
Figure 2 depicts the mean metolazone plasma concentration plotted against the time for study in young, healthy volunteers. Description of the Preferred Embodiments
Modern extrusion/spheronisation technology provides a means for obtaining small, regular spheres of a drug and therefore offered the prospect of achieving an even coating of wax or other release-controlling membrane on metolazone, whereby the desired sustained release profile could be obtained consistently and reliably with this drug. In brief, an extrusion spheronisation process typically involves the following steps: (i) form a wet, extendable blend of the drug and required excipients, (ii) extrude the blend into small, cylindrical pellets, and
(iii) roll the pellets in a spheronizer, which in essence consists of a rotating disc at the base of a short stationary cylinder, whereby the pellets are broken up and formed into small, regular spheres. The size of the resulting spherical pellets can be controlled by appropriate selection of such operational parameters of the spheronizer as disc speed, residence time in the spheronizer, spheronizer size and extrudate dimensions.
We therefore investigated the possibility of using the extrusion/spheronisation process to obtain spherical particles of metolazone for coating with wax or other release-controlling membrane. To our surprise, we found that we were quite unable to form satisfactory spherical particles of metolazone by this technique when we prepared for extrusion a blend of the drug and the usual excipients. In a conventional extrusion/spheronisation process for producing pellets of a drug, the drug is mixed with a binder such as a gum or sugar, a moisture-control agent such as microcrystalline cellulose and water so as to form a mass having the consistency of dry dough which can be extruded into small cylindrical pellets ready for spheronisation. The binder serves to hold the drug and the other excipients together during spheronisation and thus facilitate high loadings of drug, while the moisture control agent

serves the dual purpose of making the water available to plasticize the blend thereby to facilitate the extrusion but then, during spheronisation, releases the water in a slow, controlled manner whereby the spherical pellets are not disrupted by too rapid drying. After considerable experimentation we found that, although we desired a high loading of metolazone, upwards of 75%, in order to achieve a final dosage form of a reasonable size for oral administration, nonetheless the presence of a binder was a prime cause of the difficulties which we were experiencing. This discovery was quite contrary to conventional practice which teaches that a binder component is essential particularly when drug loadings of the level which we were using are required.
It is possible that the binder was in some way interfering to prevent the moisture control agent from acting in the desired way, and also it appeared that the binder was tending to stick the forming spheres together whereby large agglomerates resulted.
Based on this experimental work, we have now developed a new sustained release formulation of metolazone.
We have found that the metolazone itself acts as its own binder to enable the desired high drug loading to be achieved. We postulate that a small proportion of the metolazone dissolves during the wet blending step to form "liquid bridges" between the particles. On drying, removal of the water will leave interparticulate bonds within the structure of the pellets, whereby the pellets retain their coherency.
Thus, the present invention provides a new sustained release formulation of metolazone which comprises substantially spherical, essentially binder-free pellets containing at least 25% by weight of metolazone , preferably from 60% to 85% by weight, most preferably from 79% to 82% by weight, said pellet being individually coated with a release-controlling membrane.
The present invention also provides a method for preparing a sustained release formulation of metolazone, comprising the steps of:
(a) forming, essentially binder-free pellets containing metolazone;
(b) spheronising said metolazone pellets, and
(c) coating the resulting substantially spherical metolazone pellets with a release-controlling membrane.
The metolazone -containing pellets of the present invention can be filled into soft or hard gelatin capsules or otherwise presented in a unit dosage form for administration to a patient.
In addition to being obtainable by the more efficient, more reproducible extrusion/spheronisation technique, the present metolazone -containing pellets are found to

have excellent bioavailability and release characteristics. Indeed, by means of the present invention we have been able to produce pellets whose release and bioavailability characteristics are such as to provide a unit dosage form permitting once-a-day dosing of metolazone, rather than the twice-a-day dosing considered necessary with the present granular sustained-release formulation.
pellets of metolazone suitably have a particle size of 500-1250 microns prior to coating, preferably a particle size of 800-1000 microns. As indicated above, the particle size is mainly controlled by selection of the spheronizer and its operating parameters, but nonetheless it is good practice to sieve the spheronizer pellets in order to remove the, usually small, proportion of fines and agglomerated particles. The pellets are, as previously noted, substantially spherical, thereby facilitating an even coating of the release-controlling membrane.
In addition to the active ingredient, the spherical pellets of the present invention will generally also contain a moisture-controlling agent and a surfactant, these being ingredients usually necessary to achieve proper moisture-control for satisfactory spheronisation.
However, no separate binder needs to be included, and indeed such binder should be essentially absent, not more than about 0.1% by weight, and preferably totally absent. Although not normally preferred since it reduces drug loading, other ingredients such as hydrophilic agents, e.g. polyethylene glycol can optionally be included in the pellets if desired.
As the moisture control agent, we generally prefer to use a microcrystalline cellulose, such as those obtainable under the trade mark "Avicel" from FMC Corporation. The surfactant is preferably sodium lauryl sulphate, but other ionic and non-ionic surface active agents are also suitable.
In order to achieve the desired sustained-release properties, the spherical pellets are coated with a release-controlling membrane, such as wax as in the present granular formulation or one of the commercially available polymeric release-control materials such as those based on cellulose derivatives e.g. ethylcellulose, ethylcellulose latex, hydroxypropyl methylcelluiose, or acrylic resins e.g. combined polymers of methacrylic acid and methacrylic acid esters, or mixtures thereof. We currently prefer to use a mixture of a water-insoluble film former such as ethylcellulose and a water-soluble film former such as hydroxypropyl methylcelluiose to form a membrane which in vivo will develop pores which allow diffusion of the metolazone from the core at a controlled rate, which depends on the relative proportions of the two cellulose derivatives in the membrane. The release-control

coating may be applied by any of the techniques conventionally used in the art, preferably to a thickness of 5 to 50 microns, more usually 20 to 30 microns.
Although the metolazone -containing pellets of the present invention are generally made by conventional extrusion/spheronisation procedures (apart, of course, from the omission from the blend of a separate binder), we have found that spheronisation proceeds more satisfactorily, particularly with higher drug loadings i.e. above 50% by weight, if the blending of the wet mass prior to spheronisation and extrusion is conducted under high shear. It is considered that the application of the high shear helps to dissolve a small amount of the metolazone in the water, whereby it can then serve as the binder as described above and moreover the high shear may also help the moisture control agent to function better. In any event, in the absence of high shear during the blending step we have found it difficult to adequately control moisture levels whereby spherical pellets of desired characteristics can be repeatedly obtained without intermediate drying of the equipment. Indeed, with very high drug loadings (of the order of 80% by weight) we have found that the application of high shear during the blending is probably essential and certainly strongly recommended. A preferred procedure for making metolazone -containing pellets in accordance with the present invention is as follows:

Composition of Pellet Core
Ingredient % Composition, dry basis
General Preferred
Metolazone 65-85 80-82
Microcrystalline cellulose 15-35 18-20
Surfactant Water* 0-0.25 0.04-0.08
Binder Absent Absent
* Remove during drying stage

Composition of film coating solution
ethylcellulose 0.5-1.5 0.065-0.8
hydroxypropylmetyl cellulose 1-4 2.5-3.0
plasticizer 0.1-1 0.3-0.5
liquid carrier to 100% to 100%
Step 1
Dry blend the metolazone powder and micrc crystalline cellulose.

Add the surfactant and water to the dry blend.
Step 3
Blend the mixture to form an extrudable mass of dry dough i.e. so that it is mouldable in the
hand but breaks to give a rough fractured surface. For at least a proportion of the wet
blending, and preferably throughout, apply high shear, meaning use a high shear blender,
namely a blender having the following characteristics, viz:
(1) The material is propelled in two or more planes by two or more mixing elements. It is the interaction and working of these planes of movement against one another which results in the high shear mixing action. (Low shear blenders usually only have one mixing element and in consequence work in one plane only.)
(2) The tip speed of the mixing elements is at least 5 metres per second (low shear mixers have tip speeds of the order of 1 metre per second).
Step 4
Extrude the wet blend to form cylindrical pellets, typically of from 1 to 40 mm long, with the
majority being about 10 mm long, and with a diameter of about 0.4 to 2 mm, usually about
0.8 mm.
Step 5
Roll the pellets in a spheronizer.
As a result of the rolling motion produced within the spheronizer, the rods first break up into
shorter lengths (in the order of 1 mm long), and these particles then roll over one another and
become rounded off to yield substantially spherical pellets with a relatively tight size
distribution. Further the centrifugal forces generated within the spheronizer compress the
pellets which in consequence are densified.
The spheronizer is operated so that the pellets produced are predominantly within the range
of 500-1250 microns.
Step 6
Dry the wet spherical pellets in an oven, preferably to a moisture content of from 0.5 to 1.5%.
Lower moisture contents can present static handling problems.
Step 7
Screen the spherical pellets to obtain a batch size of 500-1250 microns.
Step 8
Prepare a dispersion of the ethylcellulose, hydroxypropyl methyl cellulose and plasticizer in
the liquid carrier.
Step 9

Coat the pellets obtained in step (7) with the release coating formed in step (8), by spray
application using a fluid bed system fitted with, for example, a Wurster column.
Step 10
Dry the film-coated pellets. Preferably, the resulting sustained-release metolazone pellets are
filled into hard gelatin capsules, either 250 mg or 500 mg per capsule. The 500 mg capsule
can provide sufficient drug to permit once-daily dosing, and indeed in some instances the 250
mg capsule can do so as well.
The invention is illustrated by the Examples which follow:
Example 1
This example describes the preparation of the currently preferred coated pellets of the present
invention, having the following composition:

Composition of Pellet Core
Ingredient % Composition, dry basis
Metolazone 80
Microcrystalline cellulose 19.94
Sodium lauryl sulphate 0.06

Composition of Coated Pellets
Ingredient % Composition, dry basis
Metolazone pellets 94.55
ethyl cellulose (10 cps) 0.72
Hydroxy propyl methyl cellulose (6 cps) 2.86
Mineral oil* 0.41
Colourant** 1.46
* plasticizer
*opaspray K-I-2506, giving a orange color
First, the preparation of the metolazone pellet cores will be described.
Metolazone raw material was first milled to break up aggregates. A weighed amount (8000 g) of the milled metolazone powder and the Avicel PH101 (1994 g) were now weighed into a high shear blender (Pharma Matrix PMA 65/25/2G, manufactured by T.C. Fielder) having two mixing blades, one larger, one smaller, working in two planes at 90(degree) to one another. The blender was operated for 5 minutes with the tip speed of the larger mixing element being 5.3 m/sec, and that of the smaller element being at the higher of its two operating speeds (corresponding to a tip speed of 22 m/sec) to ensure thorough mixing

of the metolazone and microcrystalline cellulose. Then the sodium lauryl sulphate (6 g) dissolved in 4700 ml of purified water was slowly added, the high shear blender was again operated for 10 minutes but this time with blade tip speed of the larger mixing element being increased to 10.6 m/sec, the speed of the smaller mixing element being kept at its higher setting.
The wet mass obtained was now extruded through an extruder (E140.4, manufactured by Nica Systems, Sweden) fitted with a mesh of 0.8 mn, thereby forming cylindrical pellets whose diameter was 0.8 mn and having lengths ranging from 1 to 40 mn, but with the majority of pellets being about 10 mm long.
The extruded pellets were now placed in a spheronizer (S-320, Nica Systems, Sweden) which was operated for two minutes at approximately 800 rpm. The result of this spheronisation was to form substantially spherical pellets with a size predominantly in the range 500-1250 microns. These pellets were now dried in a hot air oven for 8 hours at 50(degree)C, to reduce the residual moisture level to about 1%, and the dried pellets were then screened through a 14 mesh and 25 mesh (British Standard). The pellets obtained lay within the size range 500-1250 microns. Next the preparation of the release coating solution will be described.
Methanol (320 ml) was measured into a mixing vessel, and then the hydroxypropylethyl cellulose (28.6 g) and the ethylcellulose (7.2 g) were stirred in by means of a paddle stirrer. When complete dispersion had been achieved, mineral oil (4.1 g) and the colourant (29.74 g, containing 49.1% solids) were added to the dispersion. Finally, methylene chloride (1010 ml) was added to the dispersion and thoroughly mixed in.
The substantially spherical metolazone pellets (945.5 g) were now coated with the release coating material to form the release membrane. This was achieved in a fluidized bed. The coating material was sprayed on at the rate of 40 ml per minute. Finally, 200 ml of a methanol/methylene chloride mixture (1:3 by volume) was sprayed on to give the pellets a gloss, and the pellets were dried in a current of warm air at approximately 60(degree)C.
The resulting coated pellets had a coating thickness of approximately 1 mg per square centimetre of pellet surface area.
Comparative Example 1
Metolazone raw material was milled using an apex mill fitted with a 0.027 inch nominally rated screen. This served to break up aggregates and provide a uniform starting material.

800 g of the metolazone were then mixed with 199.4 g of Avicel PH 10) using either a low shear blender (Kenwood Planetary Mixer) or a high shear blender (Pharma Matrix PMA 55/25/2G).
0.006 g of sodium lauryl sulphate was dissolved in 300 ml water, and 10 ml of a 7.5% aqueous gelatin solution (binder solution) were added. The resulting solution was then slowly added to the metolazone /Avicel mixture and mixed in for 10 minutes, in a manner analogous to that of Example 1, using a high speed for both the low shear and high shear blenders. The resulting mass was then extruded, and spheronisation attempted.
The extrusion/spheronisation procedure was repeated after the addition of each of 2 x 100 ml additional aliquots of water.
The experiment was also repeated but using 50 ml, 100 ml or 200 ml of the 7.5% gelatin solution.
In these experiments it was found that at the higher moisture levels larger agglomerates were formed in the spheronizer, whilst at lower levels the spheroids were broken down by attrition into fines. In no instance was spheronisation satisfactorily achieved. This experiment demonstrates that the presence of the gelatin binder prevented satisfactory spheronisation even when the high shear blender was employed
No attempt was made to coat the rough pellets or fines resulting from these experiments due to their wholly unacceptable nature. Example 2
A bioavailability study was carried out in ten elderly volunteers), 7 males and 3 females, aged 60-74 years. The volunteers were divided into two groups, A and B. The volunteers in Group A took one conventional 250 mg metolazone tablet every 12 hours, whilst those in Group B took two 250 mg metolazone capsules containing coated pellets prepared as described in Example 1 together once every 24 hours. Dosing was started at 10 pm on Day 1 and blood samples were taken, to determine the plasma concentration profile under steady state conditions, at the following times after the 10 pm dose on Day 9: Conventional Tablet
0.5, 1, 2, 3, 4, 6, 9, 12 hours and at same times after 10 am on Day 10. Formulation of Invention 1, 2, 3, 4, 6,9, 12, 16 and 24 and at same times after 10 am dose on Day 10.
After an eleven day washout period, without drug administration, the two groups were crossed over, with Group A taking two formulations of this invention together once every 24 hours and Group B taking one conventional tablet every 12 hours. The blood sampling was repeated as before.

The levels of metolazone were determined by HPLC in the separated plasma.
A similar study was also carried out in eight healthy male volunteers, aged 19-27 years.
The results of this study are graphically shown in Figs. 1 and 2 of the accompanying
drawings, Fig. 1 showing the mean metolazone plasma concentration plotted against time for
the study in elderly patients, and Fig. 2 showing the same information for the study in young,
healthy male volunteers.
It has been reported that metolazone has a therapeutic plasma range of 5-10 (sup 0)g/ml, with levels above 30 (sup 0)g/ml being considered toxic. It will be seen from Figs. 1 and 2 that with both groups of patients, 2 x 250 mg capsules dosed once per day were sufficient to maintain the plasma concentration of metolazone within the therapeutically effective range. In contrast, with the conventional metolazone tablet formulation the plasma levels reached a higher peak but thereafter fell rapidly to below the therapeutically effective range, making it necessary to administer a second tablet in each 24 hours in order to maintain efficacy.

We Claim,
1. A method for preparing a sustained release formulation of metolazone, comprising the
steps of:
(a) forming essentially binder-free pellets having not more than 0.1% by weight of a binder or being totally binder free and containing at least 25% by weight of metolazone ;
(b) spheronising said metolazone pellets; and
(c) coating the resulting substantially spherical metolazone pellets with a release-controlling membrane.

2. A process as claimed in claim 1, wherein said pellets contain from 60 to 85% by weight of metolazone .
3. A process as claimed in claim 2, wherein said pellets contain from 79 to 82% by weight of metolazone .

4. A process as claimed in any one of the preceding claims, wherein said pellets also comprise a moisture-controlling agent and/or a surfactant
5. A process as claimed in claim 4 wherein said moisture-controlling agent is microcrystalline cellulose.
6. A process as claimed in claim 4 or claim 5, wherein said surfactant is sodium lauryl sulphate.
7. A process as claimed in any preceding claim, wherein said release controlling membrane comprises a mixture of water-soluble film-forming substance and a water-insoluble film-forming substance.
8. A process as claimed in claim 7, wherein said release controlling membrane comprises hydroxypropylmethyl cellulose and ethyl cellulose.
9. A process according to any preceding claim in which the formulation is presented in a unit dosage form.