Description

Technical Field

The present invention relates to oral controlled/extended release dosag forms of buspirone and its salts, applying either matrix formulations, e.g. matrix tablets or multiparticular formulations, e.g. microcapsules or coated pellets, in order to obtain a drug delivery system of buspirone which will ensure a less frequent dosing during the day, e.g. a once daily dosing with a minimum of undesired side-effects. The formulation according to the invention will also provide for a higher amount of the dose to enter the general circulation compared to a conventional immediate release tablet, still with a minimum of side effects.

Background of the Invention

The physicochemical , phaππacok netic and pharmacological properties of drugs and their products will often dictate how they should be used in

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therapeutic situation. A drug characterized by a short biological half life must be administered in short dosage intervals to maintain the plasma concentration levels and hence the pharmacological action. This may greatly disrupt the patient complience and it may cause underdosin between the dosage intervals. The ideal- oral dosage form would be a on daily formulation to maintain the therapeutic drug levels in the body for 24 hours without the risk of any adverse reactions. The use of controlled/extended release dosage forms in drug therapy has increased in the last few years and the tendency toward once a day dosing has become common. Lists over controlled release products and their design can be rather extensive (L. rowczynski, Extended Release Dosage Forms CRC-Press Inc., USA, 19S7, ISBN 0-8493-4307-0).

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There are ways of avoiding the drawback of a short biological half li (rapid elimination) by technological means, namely due to the special dosage form which would ensure the desired drug release over an exten period of time and hence slowing of the drug absorption. Over the pas two decades enormous progress has been made in developing controlled/ extended release technologies for drug compounds. The design of cont¬ rolled/extended release formulations and their technologies are well known in the art (L. Krowczynski, Extended Release Dosage Forms, CRC- -Press Inc., USA, 1987, ISBN 0-8493-4307-0).

The purpose of production and administration of controlled/extended release dosage forms as well as the conditions limiting the possi¬ bilities of the preparations have been extensively outlined in the literature (L. Krowczynski, Extended Release Dosage Forms, CRC-Press Inc., USA, 1987, ISBN 0-8493-4307-0). Some important advantages of su delivery systems are:

- reduction of the frequency of dosage during the day (increased patient compliance)

- maintenance of therapeutic plasma drug levels for the period of ti longer than the one indicated by the biological half life

- reduction of undesired adverse reactions, sometimes even toxic ones

- reduction of the total amount of drug required for a treatment by elimination of temporarily too high plasma concentrations.

Buspirone, an azaspirondecanedione, with the structural formula

8- /4-/4- ( 2-pyri mi di nyl ) l -p fperazinyl/

-8~azasp . ro( 4 , 5 ; -decane-7 , 9-di one

SUBSTITUTE SHEET

(disclosed in US 3 717634) 1s a pharmaceutically active compound which has been found to be effective for the treatment of anxiety. However, buspirone shows a very high first pass metabolism and only about 4% of therapeutic dose will unchanged reach the systemic circulation after oral administration (Hayol et.al, Clin.Pharmacol. Ther., 37, 210, 1985) Great interindividual variations regarding buspirone absorption have been observed showing a variation of the maximum plasma concentration b up to 10 fold (Ga mans et.al, American J. Med., 80, Suppl. 3B, 41-51, 1986). Two metabolites have been identified, 5-OH-buspirone which shows no pharmacological activity and l-(2-pyrimidinyl)-piperazine, i.e. 1-PP which has been found to be about 20-25% as active as buspirone per se. The biological half life of buspirone itself is very short in man, e.g. 2-11 hours, whereas the much less active metabolite 1-PP shows a more slowly elimination (Mayol et. al, Clin. Pharmacol. Ther., 37, 210, 1985). These phar acokinetic properties necessitates a rather frequent daily dosing which may have negative influences on the patient complience. Since buspirone is rapidly absorbed after an oral dose, hig plasma peak values occurs short after drug administration which can be associated with the occurence of undesired adverse events which may occur rather instantly during the first days of treatment. This can als have serious impacts on patient complience in terms of deliberated disrupture of the therapy.

The objective with this invention is to provide oral controlled/extende release dosage forms of buspirone (single unit system and multi- particulate systems) wherein a larger amount of the pharmacologically active component (i.e. un etabolized buspirone) will reach the systemic circulation compared to after administration of conventional immediate release tablets and, where such a drug delivery system shows signifi- cantly fewer adverse events (i.e. improved drug tolerability) .

Disclosure of the invention

Due to the fact that busc-irone shows a ery complicated phar acok-inetic behaviour, where the most striking phenomenon is an extensive first pas metabolism, the attempts to tackle the problem with buspirone oral absorption, e.g. to simplify the daily dosing without the risk of

obtaining underdosing between each time of administration using a drug delivery system which will generate a minimum of undesired side effect have never been undertaken.

It is well known to the man in the art that an extensive or complex metabolic pattern of a drug will make the design of an oral controlled extended release product very difficult, particularly when biological activity is wholly or partly due to metabolite, as in the case of buspirone. It has thus been stated in the literature that differences systemic availability due to metabolism during the absorptive process can be greater for controlled/extended release drug dosage forms than for immediate release drug products. Hence, it has been claimed that drugs which undergo extensive first pass clearance are unsuitable for oral controlled/extended release dosing (J.R. Robinson and V.H.L. Lee, Controlled Drug Delivery. Fundamentals and Applications, Marcel Dekker Inc., USA, 1987, ISBN 0-8247-7588-0). It has also been shown in the literature that metabolism of a drug, e.g. alprenolol, was more comple when it was administered in a controlled/extended release form than in conventional tablets (R. Johansson, C.G. Regardh and J. Sjδgren, Acta Pharm. Suec, 8,59 (1971)). Many other examples of similar matters hav been reviewed in the literature (J.R. Robinson and V.H.L. Lee, Controlled Drug Delivery. Fundamentals and Applications, Marcel Dekker Inc., USA, 1987, ISBN 0-8247-7588-0).

Buspirone shows an extensive first pass metabolism with a ten-fold variation between subjects. Hence, due to this metabolic pattern in relation to the above mentioned examples and general statements from t literature regarding the suitability for such a drug to be used for a controlled/extended release dosage form is probably the reason why no prior attempts have ever been made to design an oral controlled/ extended release product of buspirone.

According to the invention it has now been found that it is possible to extend the oral absorption phase of busoirone without the formation of too high plasma peak values by administering buspirone in controlled/ extended release formulations. The plasma concentrations of buspirone- were found to be extended and constant for a period of at least 18 hour

after a 30 mg single dose and, during a 24 hour test period in vivo, a very high tolerability was observed compared to the administration of conventional buspirone tablets (3 x 10 mg). Furthermore, the mean relative extent of buspirone bioavailability was found to be increase by 5-6 times compared to the conventional dosage form of buspirone.

The present invention provides an improved oral delivery system for buspirone compared to conventional immediate release formulations. Different technologies can be applied for controlling and extending th release of buspirone (and hence its absorption in vivo) such as matrix formulations and ulticompartment formulations (capsule or tablet containing pellets or microcapsules). This invention relates to variou in vitro release time courses within each kind of technology by the application of various types and combinations of exipients and polymer The present invention relates to the combination of buspirone to all kind of oral controlled release formulations known in the art which ar able to show a total in vitro dissolution time between 6 and 24 hours for at least 80 per cent of the drug content.

The in vitro dissolution time is measured by means of the USP XXI padd method at 50 or 100 rpπ. This method gives results in accordance with the flow through method using water at a flow rate of 16 ml/minute.

By either embedding the buspirone compound into a matrix formulation o overcoating it into a microcapsule formulation or both in order to control or extend the release, the following advantages are obtained compared to when conventional immediate release tablets are used:

- a slower in vivo absorption of buspirone and hence lower plasma pea values which hence reduce the occurrence of undesired side effects. This also means that the plasma peak values and the rate of increas of the plasma concentration for the less active metabolite 1-PP will be lower.

- prolonged and constant buspirone plasma concentrations over 24 hou which will avoid underdosing between dosage intervals.

- a significant increase of the relative extent of buspirone bioavailability (i.e. the therapeutically relevant component).

- much higher tolerability of the drug, i.e. much less side effects

5

- a once daily dosing of buspirone which together with the higher tolerability definitely will increase the patient complience

- a lower cost for society since lower amount of buspirone will

10 probably be needed due to the superbioavailability mentioned above.

Furthermore, the tablet formulations according to the present invention ^• can be made smaller in size compared to the current market image of buspirone (BUSPAR*^ Bristol-Meyers, USA) even though they contain as

15. much as three times the amount of buspirone. This will be another advantage regarding patient complience since it must be much easier to swallow eg. a 6-8 mm round tablet once daily containing e.g. 15-30 mg buspirone compared to 1-2 tablets with a size of e.g. 6 x 10 mm 3 times daily (BUSPAR®, Bristol-Meyers, USA).

20

Any salts of the active substance can be used, for instance acetate, benzenesulfonate, benzoate, bicarbonate, bitartrate, bromide, calcium edetate, camsylate, carbonate, chloride, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate,

?5 gluta ate, glycollylarsaπilate, hexylresorcinate, hydrabamine, hydrobro ide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, malate, .maleate, andelate, esylate, methyl- bromide, methylπitrate, methylsulfate, mucate, napsylate, nitrate, pamoate, (embonate), pantothenate, phosphate/diphosphate, polygal- 0 acturonate, salicylate, stearate, subacetate, succinate, sulphate, tannate, tartrate, teoclate, triethiodide.

SUBSTITUTE SHEET

Coating and matrix materials for obtaining controlled/extended release

The formation of microencapsulated material and matrix adjuvant is well known in the art and does not form any part of the present invention.

As coating or matrix adjuvant any coating or matrix material can be used. The type of material will be chosen depending on the desired controlled release time-function i.e. whether it will be a dosage form having a 6, 12 or 24 hours release time in vitro. The choice of coating or matrix material will in either case be obvious to the man skilled in the art.

Coating and matrix materials to be used are for instance

Polymers: synthetic polymers of polyvinyl type, e.g. poly vinylchloride,polyvinylacetatε and copol mers thereof, poly- vinylalcohol,polyvinylpyrrolidone.

Polyethylene type, e.g. polyethylene, polystyrene.

Po.y ers of acrylic acid or acrylic acid ester type, e.g. methylmetacrylate or copolymers of acrylic monomers.

Biopolymers or modified biopolymers of cellulose, e.g. ethylcellulose, cellulose acetate phtalate, cellulose acetate, hydroxy propyl cellulose, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, ethylcellulose, microcrystalline cellulose, Na-carboxymethyl cellulose.

Shellac

Gelatin

Fats, oils, higher fatty acids and higher alcohols e.g. aluminium onostearate, cetylalcohol, hydrogenated beef tallow,

hydrogenated castor oil, 12-hydroxystearyl alcohol, glyceryl mono- or dipal itate, glyceryl mono- di-, or tristearate, yristyl alcohol, stearic acid, stearyl alcohol.

Polyethyleneglycols

Waxes e.g. bees wax, carnauba wax, Japan wax, paraffin, spermaceti, synthetic wax.

Sugars and sugar alcohols e.g. mannitol, sorbitol, sucrose, xylitol, glucose, maltose.

The polymers mentioned above can be used depending on the technique applied as coating agents, matrix adjuvants or pharmaceutical binders. ^' Whether the polymer will be a matrix adjuvant or a pharmaceutical binde will be dependant on the amount of polymer in the formulation.

Any combinations of the above mentioned polymers, fats and waxes can be used for encapsulation purposes as well as for matrix formation, viz. different polymers can be mixed, a polymer can be mixed with a fat or wax etc.

The encapsulation of the drug can be achieved in the form of microcapsules, but the encapsulation is not restricted to the micro size.

The multiparticulate dosage forms, i.e. microcapsules or coated pellets as well as the matrix tablets useful for the present invention can be prepared by any of several acknowledged production processes including conventional granulation and tabletting of matrix tablets, pan coating, prilling, extrusion and spheronization, fluid bed processes, spray drying, spray chilling, coacervation and other processes.

Microcapsules or coated pellets

Microcapsules or coated pellets are defined as a solid or liquid core enclosed in a coating. The coating may also be referred to as the wall or shell. Various types of icrocapsule structures can be obtained depending on the manufacturing process e.g. mononuclear spherical, multinuclear spherical, multinuclear irregular, encapsulated mononuclear capsules, dual-walled microcapsules etc. Where no distinct coating and core region can be observed, the anologous terms are microparticles, iπicrospheres, micromatrices, micro beads. The microcapsules or pellets usually have a particle size between 1 and 2000 microns.

The microcapsules or coated pellets of buspirone and its salts can be filled into empty hard gelatine capsules to an extent corresponding to the desired dose or they can be gently compressed into a tablet by using suitable tablet excipients.

Buspirone or a salt thereof could be mixed with a pharmaceutical binder to form micropellets which are then cpmpressed into tablets.

The oral formulation of the invention could comprise micropellets which are then overcoated wiht a pharmaceutically acceptable coating adjuvant prior to being compressed into tablets.

The micropellets can also be filled into capsules.

The oral formulation of the invention could comprise microspheres which are then overcoated with a pharmaceutically acceptable coating adjuvant prior to being filled into capsules.

Matrix formulations

Matrix formulations are defined as a drug embedded in insoluble excipients in order. o achieve extended release by a continuous leaching of the drug from "the inert matrix core. The release mechanism often follows the square root law of Higuchi ( (t -law). This term also applies to a matrix built of hydrophilic substances which in contact with water

SUBST

form a gel of high viscosity.

Preferred embodiments

A preferred embodiment of the present invention is obtained when bus¬ pirone hydrochloride is embedded in polyvinyl chloride and polyvinyl acetate and then compressed into a tablet formulation using magnesium stearate as lubricant (round tablet, 6-8 mm in diameter).

Other preferred embodiments are obtained when buspirone hydrochloride is embedded in polyvinyl chloride and ethyl cellulose by the addition of hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose or paraffin. The material is then compressed into tablets using magnesium stearate as lubricant.

• Still other preferred embodiments are when buspirone hydrochloride is mixed with a sugar derivative e.g. lactose and/or a cellulose derivative e.g. microcrystalline cellulose to obtain uncoated microspheres by means of extrusion and spheronization. The microspheres are then overcoated with e.g. ethyl cellulose using a suitable plasticizer e.g. triethyl citrate. The microcapsules can be filled into empty hard gelatine capsules.

Other preferred embodiments are when buspirone is suspended in a wax melt, e.g. carnauba wax, bees wax etc. and then spray chilled into microspheres. The spherical particles can then be overcoated with a fat or fatty acid, polyethylene glycol or a low melting wax by suspending the microspheres in the low melting excipient and then once again spray chill the slurry into microcapsules.

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Best mode of carrying out the invention

Example 1

Buspirone hydrochloride was dry mixed with polyvinyl chloride. The powder mixture was then granulated with a solution of polyvinyl acetate in ethanol. After drying and milling, the granulation was compressed into 7 mm round tablets.

The buspirone controlled release tablets consist of (mg/tablet).

Buspirone hydrochloride 30

Polyvinyl chloride 120 Polyvinyl acetate (C10-V7) 11

Magnesium stearate 1.6

The in vitro dissolution was investigated ^" in water by means of the USP XXI paddle method at different agitation conditions. The results ar shown in Table 1.

Table 1

Time (hours) Range (ϊ dissolved, n=6)

50 rp 100 rpm

1 34-35 32-39

3 57-58 53-57

5 71-73 67-71

8 84-38 81 -57

12 92-96 ^' 90-95

This particular^ controlled release formulation of buspirone shows a 12 hour release time profile. As can be seen, a very uniform in vitro dissolution behaviour with a low interindividual variation between the six different tablet units are obtained. Hence, the design of the dosa form seems to ^' be ery robust in terms of in vitro dissolution charac¬ teristics.

The in vivo absorption and drug tolerability of this particulary formulation of buspirone were studied in six healthy subjects. As a reference, the same dose of conventional immediate release buspirone tablets was used, e.g. 3 x 10 mg, BUSPAfoH Bristol-Meyers, USA.

Table 2 shows typical plasma concentration versus time courses of buspirone for the two products tested in two different subjects. As can be seen, significant different plasma profiles are obtained with the tw buspirone products. The invented controlled/extended release dosage for of buspirone shows much lower plasma concentration peaks, a slower rate of absorption and much more extended plasma concentration versus time courses compared to the conventional tablet formulation of buspirone. Buspirone can be detected in plasma 24 hours after administration of th invented formulation whereas no detectable buspirone concentrations can be found 4 to 8 hours after dosing of the conventional immediate releas tablets.

Table 2

Invented product (ng/ml) Conventional product (ng/ml) Time (h) Subj. 1 Subj. 4 Sub . 1 Sub . 4

ND = not detected

* = below the lowest standard calibrator used in the assay (0.5 ng/m

Table 3 shows the relative extent of buspirone bioavailability for t invented controlled/extended release tablet compared to the conventi formulation. Dose = 30 mg.

Table 3

Subject No el. extent of buspirone bioavailability for the invented formulation

1 16.8

2 11.9

3 1.2

4 4.7

5 1.4

6 0.4

As can be seen, in 5 out of 6 subjects, a significant increase in buspirone bioavailability is obtained if the rate of drug release fro ^' 'the dosage form is decreased by means of the invented product design. Hence, the buspirone has become superbioavailable by means of the invented controlled/extended release dosage form. Even if significant higher amounts of buspirone will enter the general circulation during

24 hour time period compared to after administration of conventional tablets, an improved ^" drug tolerability is obtained by administering buspirone in a controlled/extended release dosage form according to t present invention.

Table 4 shows the observed side effects in each subject at a single d of 30 mg.

t ab le 4

Adverse experience (severity)*

Invented product Conventional according to product

Subject No Example 1

Frontal headache (2) None

None Dizziness & light-headed (2)

None Dizziness & paraesthesia (1)

4 None Dizziness (2)

5 None Dizziness & para¬ esthesia in both hands, dizziness postural in natur Nausea on sitting up (3)

None None

* (1) = mild, (2) = moderate, (3) = severe

It is very obvious that the present invention will be a great improve¬ ment in the therapeutic application of buspirone in terms of drug tolerability.

As mentioned above, the extent of buspirone bioavailability was significantly Improved. However, another positive effect caused by t present Invention of buspirone Is a decrease of the bioavailability the less active metabolite 1-PP. The present invention creates much lower plasma peak values of 1-PP and a slower rate of the increase o its plasma concentrations which may also be a contributing factor for the good tolerability obtained after administration of the present buspirone invention. Table 5 summarizes the relative extent of 1-PP bioavailability after administration of the buspirone controlled/ extended release tablet according to Example 1, compared to a con¬ ventional tablet formulation.

Table 5

Subject No Rel. extent of 1-PP bioavailability for invented product

0.7

0.5

0.4

0.9

5 0.7

6 1.1

Example 2

Buspirone hydrochloride was dry mixed with polyvinyl chloride. The powder mixture was then granulated with polyvinyl acetate dissolved i ethanol. After drying and milling, the granulation was compressed int round matrix tablets with a diameter of 8 mm.

The buspirone controlled release matrix tablets consist of (mg/tablet)

Buspirone hydrochloride 30

Polyvinyl chloride 160

Polyvinyl acetate 20 Magnesium stearate 2.1

The in vitro dissolution was determined in water by means of the USP Paddle method at various agitation conditions, see Table 6.

Table 6

Time (hours) Range (% dissolved, n=6)

50 rpm 100 rpm

1 22-23

3 36-39

5 48-50

8 miss ing

12 68-71

15 81-85

20 88-93

24 >S0

This particularly controlled release formulation of buspirone shows a 24 hour release time course. As can be seen 1n Table 6, this formulat of buspirone shows a very uniform in vitro dissolution behaviour with low interlnc'ividual variation between the six different tablet units which is in good agreement with the data shown in Example 1 for a 12 hours controlled release matrix tablet. Hence, as was mentioned before, the principle of embedding buspirone into a polyvinyl chlorid polyvinyl acetate matrix will produce a robust and reliable drug delivery system which is unaffected by the hydrodyna ic intensity.

The in vivo absorption and drug tolerability were also investigated f this 24 hour release time formulation of buspirone. Six healthy subje participated in the study using conventional immediate release tablet (3 x 10 mg), BUSPAFrH Bristol-Meyers, USA as reference.

Table 7 shows typical plasma concentration versus time courses of

__• buspirone in two subjects after administration of the invented con¬ trolled release formulation. As a reference, plasma concentration ver time courses are also shown after administration of conventional bus- pirone tablets (BUSPAR^; Bristol Meyers, USA) at a single dose of 30 As can be seen, highly different plasma profiles were obtained. Once again, the invented product of buspirone shows much lower plasma con¬ centration peaks, a slower rate of absorption and much more extended plasma concentration versus time courses compared to the conventional tablet formulation. Thus, even if the in vitro dissolution time is increased from 12 hours to 24 hours (cf. Example 1), a sufficient absorption of buspirone is achieved. After 24 hours, significant plas concentration levels are found in the two subjects after administrati of the invented buspirone formulation, whereas no detectable concen- trations or low ones were obtained for the conventional dosage f 4 to 8 hours after dosing.

Table 7

ND = not detected

* = below the lowest standard calibrator used in the assay (0.5 ng/

Table 8 shows the relative extent of buspirone bioavailability for t invented 24 hour release formulation of buspirone compared to the

_& ^• conventional tablet formulation (BUSPAR^, 3 x 10 mg, Br stol-Meyers,

USA).

Table 8

Subject No Rel. extent of buspirone bioavailability for the invented formulati

1 Missing data

2 8.2

3 1.3

4 6.3

5 1.7

6 0.4

An increase of buspirone bioavailability can be seen for the invented 24 hour controlled/extended release formulation which is in agreement with the absorption data found for the 12 hour release formulation in Example 1. The plasma concentrations in subject no 1 were found to be detectable but below the lowest standard calibrator used in the assay, i.e. 0.5 ng/ml. This is the reason why the relative extent of buspiron bioavailability has not been given in Table 8. However, if the raw dat are used in a calculation, a value of 2.8 is found for subject no 1. I is only in subject No 6 where a lower bioavailability can be seen whic also is in agreement with the data shown in Example 1 (the same health subjects were used in both studies).

The adverse experiences obtained for the different buspirone formulations after a single dose of 30 mg are reported in Table 9.

Table 9

Subject No Adverse experience (severity)*

Invented product Conventional according to Example 2 product

1 None None

2 None Dizziness & light¬ headed (2)

None Dizziness & para- esthesia (1)

4 None Dizziness (2)

5 None Dizziness & para- esthesia in both hands (fingertips only), dizziness postural in nature. Nausea on sitting up (3)

None None

* (l) = mild (2) = moderate (3) = severe

Once again, it is er obvious that the present invention will be a great improvement in the therapeutic application of busr-- oπe in term of drug tolerability.

Table 10 shows the corresponding bioavailability data for the 1-PP metabolite.

Table 10

Subject No Rel. extent of 1-PP bioavailability for the invented product

1 0.44

2 0.16

3 0.16

4 0.70

0.78

1.02

The results in Examples 1 and 2 have shown that buspirone controlled extended release formulations can be designed either as 12 hours or 24 hours release products. For both kinds of products, significantly higher extent of buspirone bioavailabilities and a very low frequenc side effects were obtained compared to a single dose administration conventional tablet formulation. Hence, the most optimum use of bus- pirone in a therapeutic situation would be the application of a con¬ trolled/extended release product. Both a 12 and a 24 hours release formulation can be used for obtaining an extended plasma concentrati _____ versus time course suitable for a once daily dosing. The present

formulation of buspirone. These advantages of the present invention compared to the current conventional βarket formulation (tablets) of buspirone will definitely make therapy easier for the patients and hence, an increase in patient complience is to be expected.

^"

Exam le 3

Buspirone hydrochloride was dry mixed with polyvinyl chloride. The powder mixture was granulated with a solution of polyvinyl acetate dissolved in ethanol. After drying and milling, the granulation was compressed into round matrix tablets with a diameter of 6 mm.

The buspirone controlled/extended release tablets consist of (mg/tabl

Buspirone hydrochloride 15

Polyvinyl chloride 80

Polyvinyl acetate 7.3

Magnesium stearate 1.0

The in vitro dissolution data are presented in Table 11 using the USP XXI paddle method at 50 rpm (water).

Table 11

Time (hours) Range (ϊ dissolved, n=6)

3 50-57

6 67-77

12 85-96

The present formulation relates to a 12 hours release product contain 15 mg buspirone hydrochloride per tablet.

Example 4

Buspirone hydrochloride was dry mixed with polyvinyl chloride and sod carboxymethyl cellulose. The powder mixture was granulated with a solution of ethyl cellulose 10 cps dissolved in ethanol. After drying and milling, the granulation was compressed into tablets using magnes stearate as lubricant (8 mm round tablets).

The buspirone controlled/extended release tablets consist of (mg/tabl

Buspirone hydrochloride 30

Polyvinyl chloride 145 Ethyl cellulose 10 cps 10

Sodium-carboxymethyl cellulose 15 Magnesium stearate 1.95

Table 12 shows the in vitro dissolution characteristics for this particulary controlled release formulation of buspirone using the USP XXI paddle method at 50 rpm (water).

Table 12

Time (hours) Range (X dissolved, n=3)

1 26-32

2 47-52

6 85-94

As can be seen, the above formulation shows a 6 hours release time course of buspirone in vitro.

Example 5

Buspirone hydrochloride was dry mixed with lactose and microcrystall cellulose. Water was added and the wet powder mass was extruded in a NICA-extruder using a 1 am screen. The extrudates were spheronized o maru erizer plate into microspheres to a size range of 0.8-1.4 m. T wet microspheres were dried and then overcoated with ethyl cellulose 10 cps in a fluid bed apparatus. The ethyl cellulose was dissolved i 6/4 mixture of methylene chloride and ethanol. Triethyl citrate was as plasticizer in the polymer film.

The buspirone controlled/extended release microcapsules consist of t following. A 30 mg dosage strength (i.e. a hard gelatine capsule) is used in this particulary Example. However, lower as well as higher dosage strengths can easily be obtained by decreasing or increasing amount of microcapsules administered e.g. in a hard gelatine capsule

Table 13 shows the in vitro dissolution results for the buspirone controlled/extended release microcapsules using the USP XXI paddle method at 50 rpm (water).

SUBSTITUTE SHEET

Table 13

Time (hours) Range {% dissolved, n=3)

1 20-22

3 51-53

6 72-74

12 88-90

As can be seen, buspirone can be formulated into a multiparticular _, controTled/extended release formulation showing, as in this Example, 12 hour release time course in vitro.