WO1998034598A2

WO1998034598A2 - Homogeneous granulated formulations for dose sipping technology

Info

Publication number: WO1998034598A2
Application number: PCT/EP1998/000797
Authority: WO
Inventors: Jan Willem Groenendaal
Original assignee: Gist-Brocades B.V.
Priority date: 1997-02-07
Filing date: 1998-02-06
Publication date: 1998-08-13
Also published as: WO1998034598A3; AU6496498A

Abstract

A number of new homogeneous granulated formulations for Dose Sipping Technology has been provided, used for administering pharmaceutically active material, for instance anti-infective agents such as antibacterial antibiotics, which are co-formulated with a number of excipients.

Description

HOMOGENEOUS GRANULATED FORMULATIONS FOR DOSE SIPPING TECHNOLOGY

Technical field

The present invention relates to homogeneous granulated formulations and to a process to prepare the same, suitable for a Dose Sipping device.

Background of the invention

It is known that many patients often have difficulties in swallowing medicine in tablet or capsule form. These solid dosage forms are for many patients difficult to swallow because of their size, especially for children or the elderly. The pharmaceutically active agent itself is usually rather distasteful for instance with amoxycillin, also contributing to the swallow difficulties. To overcome these drawbacks other dosage forms, like suspensions have been developed to facilitate administering of pharmaceutically active agents. A suspension has to be prepared shortly before delivery to the patient and has to be measured with a spoon or a cup with inherent inaccuracy of the dosage . New dosage forms are developed to meet this challenge, in particular homogeneous granulated formulations are manufactured to be used together with a Dose Sipping device, meet various requirements necessary for a working composition of a granulate, the granulate must possess appropriate physico-chemical properties relating to hardness, stability, friability, disintegration time and so on. In combination with a specially designed Dose Sipping device as described in the international application WO97/03634 it allows patients to take the pharmaceutically active material without all the drawbacks as mentioned above. Administration is even possible whilst lying in bed without the need to sit upright completely. In general a pharmaceutically active material is preferably a dry pharmaceutical dosage form such as

- oral tablets which can be used to swallow as a whole, to chew, or to put in an aqueous liquid to disperse the tablet by disintegration or effervescent action after which the suspension or solution can be swallowed,

- a hard gelatin capsule which is intended to swallow as a whole,

- a mixture of solid particles which are first dispersed or dissolved in a liquid after which it is swallowed as a single dose or only a measured part is swallowed and the remaining part of the suspension is stored in a cool place for a longer period as multiple dosage form. The manufacture of the oral tablets is done by compacting mixtures of particles. The particles can be of primary form like crystals or can be agglomerated to clusters of primary particles. These agglomerates are often called granules or granulates. A tabletting mixture consists of an active ingredient and several or one of the following excipients : - diluents, to dilute the concentration of the active material ,

- (dry) binders, which increases the plastic deformation of the mixture,

- flowing agents or glidants, which increases the flowability of the mixture,

- lubricants, to lubricate the metallic parts of the tabletting tools used,

- disintegrants, which increases the rate of disintegration of the compact or granule, - flavours and sweeteners, which will improve taste,

- effervescent additives, used for developing C0₂,

- solubilizing agents, which help to wet the particles and let fluids penetrate into the agglomerate of particles.

The hard gelatin capsules are filled with pure active ingre- dients or mixtures, granulates of active material and excipients particles as mentioned above under tablet mixture. Solid mixtures of particles consist of mixtures of active material and excipients particles like those mentioned above under tablet mixture, excluding dry binders and lubricants. The solid mixtures can consist of granules or partly of granules and powder excipients. For solid mixtures a good flowability is required because they are used for filling with the aid of specifically designed filling equipment in small bottles for multiple dose applications or small bags for single dose. Because tabletting, capsule filling and in most cases solid mixture filling are high speed processes, the requirements for mixtures concerning flowability and low dust amount are high. The flowability of mixtures can be increased by the use of granulates . These granulates are made before the actual tabletting, capsule or solid mixture filling by means of specific techniques called dry or wet granulation.

Dry granulation is the formation of agglomerates without the use of a liquid, the agglomerates are made by dry compaction of the ingredients, followed by breaking the large compacts and finally by sieving out the required particle size. Wet granulation is the formation of agglomerates according to the successive steps: mixing of the ingredients; adding a granulating fluid; drying the wet mass during which the actual agglomeration takes place and finally sieving out the required particle size.

State of the art

A way to ensure a proper release of the pharmaceutically active material from the Dose Sipping device by ALZA, indica- ted as above, or a similar device described in for instance the American patents US 4,792,333 or US 4,981, 468, is to avoid blocking of the straw and to avoid entry of the dry medicine in the oral cavity of the patient. With the aid of several excipients co-formulated within the granule, granu- lation formulations have been developed which meet amongst others the requirements set .

In International patent application W091/16893 a granule, containing β-lactam as an active material, combined with an effervescent adjuvant used for aqueous suspensions has been described. Furthermore patent application W092/19227 also discloses a tablet, consisting of a medicament and optional intra- and extra-granular disintegrants . Furthermore, in international patent application W094/27557 a β-lactam tablet, which comprises thermal infusion granules obtained using hydrophobic wax, has been described. The resulting tablet is bi-layered, coated with a hydrophobic wax. Besides that patent application W095/28927 describes a tablet formulation, comprising amoxycillin trihydrate and clavulanate coated by polymers. Microcrystalline cellulose is used as a disintegrant. Also in patent application WO96/04907 sustained-release tablets containing β-lactam and a β-lacta- raase inhibitor have been described. Finally patent application WO96/04908 describes a tablet consisting of two layers with different compositions inclusive a film coating. The granulates of the patents mentioned above are not homogeneous and they are further processed by coating or tabletting. Also disintegrants are used frequently.

It is evident that nothing in the prior art does suggest a manufacturing of granulates having the specific characteris- tics which enables them to be used in a Dose Sipping device such as the one described in this invention. Summary of the invention

According to the present invention a new granulate composition of homogeneous granulated formulations for oral delivery, preferably by means of a Dose Sipping device has been provided for. These granules are homogeneous, with a particle size of 125 to 1000 μm, permitting the formulations to be wetted and admix or dissolve after contact with a fluid. Preferably, the size of the particles is from 125 to 750 μm, whereby each particle comprises a blend of pharmaceutically active materials and one or more excipients allowing the granulates to be wetted and admix better with a fluid. The pharmaceutically active materials should already be wetted, in admix or dissolved before entering the oral cavity of the patient, avoiding a gritty feeling, bad taste and inhalation.

These granules may be manufactured by wet or dry granulation, such as slugging and/or dry roller compaction. During the process of this invention preferably slugging and dry roller compaction are used. The pharmaceutically active material comprises the group of antibacterial antibiotics which are co-formulated with a number of excipients into a homogeneous blend. Suitable for this purpose is an anti- infective agent selected from any of the groups of antibacterial antibiotics consisting of Cephalosporins or related β-lactams. The β-lactams are for instance penicillin V potassium salt or acid, amoxycillin trihydrate, ampicillin trihydrate and for instance Cloxacillin Sodium, Flucloxacil- lin Sodium and Dicloxacillin Sodium, and Cephalosporins are for instance Cephalosporin, Cephalexin, Cefaclor and Cefa- droxil . Furthermore the pharmaceutically active material comprises Tetracyclines, for instance Tetracycline, Oxytetracycline, Doxycycline, Minocycline, Chlortetracycline and Demeclocycline or any acid salt, for instance a chloric salt, thereof and also Macrolides, for instance Erythromycin, Clarithromycin, Roxithromycin and Azithromycin, or any stearate and/or any estolate thereof. All antibiotics are optionally combined with β-lactamse inhibitors, such as sulbactam or clavulanic acid.

The excipients used for coformulation are mannitol and/or sorbitol which are cool sweeteners and dry binders, rice starch and Emcompress^® (Edward Mendell Co Inc) as dry binders. Furthermore magnesium stearate and Lubritab^® (Edward Mendell Co Inc) are used as lubrificants for the compressing tools. Aerosil^® was used as a flowing aid. The resulting granules compositions have a good flowability and the right disintegrating characteristics to admix, dissolve without either blocking the straw or allowing dry material to enter the oral cavity of the patient.

Detailed description of the invention

The invention provides for homogeneous granulated formulations of pharmaceutically active materials, characterized by the preparation of a blend of pharmaceutically active material and one or more excipients, wherein the granulates comprising said blend have a particle size from 125 to 1000 μm, preferably a particle size of 125 to 750 μm, permitting the formulations to be wetted and admix with a fluid, preferably by means of a Dose Sipping device, suitable for oral delivery. This device has been described in the patent appli- cation WO 97/03634. It is characterised in generalised terms as a formulation chamber, having a first end and a second end, containing a pharmaceutically active material and a retainer for preventing release of the pharmaceutically active material from the first end but permitting fluid entry into the chamber. The retainer could be any known means of separation into two compartments, for example a valve, grid, ball or piston but is further characterised as a one-way movable plug which is deformable, allowing a fluid to bypass. The Dose Sipping device is often referred to as a straw.

To meet the various requirements as mentioned in the Background part of the present application, pharmacy has a great variety of excipients at its disposal.

The disintegrants are carefully selected because a specific dissolvability is required in order to acquire complete admixture or dissolving before the mixture reaches the oral cavity of the patient, but in the mean time does not block the passage of fluid into the formulation chamber. It will be clear to a person skilled in the art that the above described physical action is strongly influenced by the composition of the particles. Therefor special attention is given to the necessary qualifications of the selected excipients. These are such that it operates without blocking the straw and/or allowing dry powder to reach the end of the formulation chamber or accidentally enter the oral cavity, causing a gritty feeling or choking. Blocking of the fluid passage, is mainly due to the swelling behaviour of the excipient itself, blocking the mini pores for fluid to pass. In order to obtain a granulate with optimal characteristics, a wide range of excipients and different compositions were manufactured and tested. In general a pharmaceutically active material used for oral delivery is preferably formulated as a dry pharmaceutical dosage form such as

- a hard gelatin capsule which is intended to swallow as a whole,

- a mixture of solid particles which are first dispersed or dissolved in a liquid after which it is swallowed as a single dose or only a measured part is swallowed and the remaining part of the suspension is stored for a longer period as multiple dosage form.

The manufacture of the oral tablets is done by compacting mixtures of particles. The particles can be of primary form like crystals or can be agglomerated to clusters of primary particles. These agglomerates are often called granules or granulates. A tabletting mixture consists of an active in- gredient and several or one of the following excipients; diluents, to dilute the concentration of the active material, such as calcium carbonate, calcium sulphate, compressible sugar, confectioner's sugar, dextrates, dextrin, dextrose, dibasic calcium phosphate dihydrate, lactose, magnesium carbonate, maltodextrin, mannitol, microcrystalline cellulose, polymethacrylates, powdered cellulose, pregelatinized starch, sorbitol, rice starch, sucrose, tribasic calcium phosphate, - (dry) binders, which increase the plastic deformation of the mixture, such as acacia, alginic acid, carbomer, carbo- methylcellulose sodium, dextrin, ethylcellulose, gelatin, guar gum, hydrogenated vegetable oil, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, liquid glucose, magnesium aluminium silicate, maltodextrin, methylcellulose, polymethacrylates, povidone, pregelatinized starch, sodium alginate, rice starch, zein,

- flowing agents or glidants, which increase the flowability of the mixture, such as colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, rice starch, talc, tri basic calcium phosphate,

- lubricants, to lubricate the metallic parts of the tabletting tools used, such as calcium stearate, glyceryl mono- stearate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, light mineral oil, magnesium stearate, mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl sulphate, sodium stearyl fumerate, stearic acid, talc, zinc stearate,

- disintegrants, which increase the rate of disintegration of the compact or granule, such as alginic acid, carboxymethyl - cellulose calcium or sodium, colloidal silicon dioxide, cros- carmellose sodium, crospovidone, guar gum, low substituted hydroxypropyl cellulose, magnesium aluminium silicate, methylcellulose, microcrystalline cellulose, polacrilin potassium, powdered cellulose, pregelatinized starch, sodium alginate, sodium starch glycolate, rice starch, flavours and sweeteners, which will improve taste, such flavouring agents are: maltol, ethyl maltol, ethyl vanillin, fumaric acid, malic acid, menthol, vanillin, a number of concentrated and purified flavours from vegetable origin are microencapsulated powders, sweeteners such as compressible sugar, confectioner's sugar, dextrose, glycerin, lactose, liquid glucose, maltitol solution, mannitol, sorbitol, sucrose, xilytol, the more intense sweeteners are acesulfame potassium, aspartame, saccharin, saccharin sodium, sodium cyclamate, - effervescent additives, used for developing C0₂, such as citric acid, sodium bicarbonate, sodium citrate, tartaric acid,

- solubilizing agents, which helps to wet the particles and let fluids penetrate into the agglomerate of particles, such as cyclodextrins, lecithin, sucrose, mannitol, sorbitol.

The hard gelatin capsules are filled with pure active ingredients or mixtures, granulates of active material and excipients particles as mentioned above under tablet mixture. Solid mixtures of particles consist of mixtures of active material and excipients particles like those mentioned above under tablet mixture, excluding dry binders and lubricants. The solid mixtures can consist of granules or partly of granules and powder excipients. For solid mixtures a good flowability is required because they are used for filling with the aid of specifically designed filling equipment in small bottles for multiple dose applications or small bags for single dose.

Because tabletting, capsule filling and in most cases solid mixture filling are high speed processes, the requirements for mixtures concerning flowability and low dust amount are high. The flowability of mixtures can be increased by the use of granulates . These granulates are made before the actual tabletting, capsule or solid mixture filling by means of specific techniques called dry or wet granulation. Dry granulation is the formation of agglomerates without the use of a liquid, the agglomerates are made by dry compaction of the ingredients, followed by breaking the large compacts and finally by sieving out the required particle size. Wet granulation is the formation of agglomerates according to the successive steps: mixing of the ingredients; adding a granulating fluid, containing a dissolved binder like cellulose derivatives; screening and drying the wet mass during which the actual agglomeration takes place and finally a second screening by sieving out the required particle size to discard lumps. Compositions of granulates manufactured as described, containing both active material and any excipients to be used, and/or part of the excipients can be added afterwards as separate granules and mixed later. Some of the excipients to be used are commercially available as granulates and can be mixed with separately manufactured granules containing the active material. The granulated formulations manufactured for this invention, are homogeneous granules with a particle size of 125 to 1000 μm, permitting the formulations to be wetted and admix after contacting with a fluid. Preferably, in combination with a Dose Sipping device, the particle size is from 125 to 750 μm allowing the granulates to be wetted and admix better with a fluid. Therefor, the pharmaceutically active materials are already in admix or dissolved before entering the oral cavity of the patient, avoiding a gritty feeling, bad taste and inhalation. The manufacture of the before mentioned granulated formulations, is characterised by dry granulation such as slugging and/or dry roller compaction of said blend, or wet granulation and further sieving of said blend. Wet granulation procedure is described as follows. An anti-infective is mixed with a liquid containing a dissolved binder like cellulose derivatives. The wet mass is screened and dried after which as second screening is performed to discard lumps. In this invention preferably slugging and more preferably dry roller compaction are used. The pharmaceutically active material as used in the Dose Sipping device mentioned above, comprises the group of antibacterial antibiotics wherein the pharmaceutically active materials are co-formu- lated with a number of excipients into a homogeneous blend.- The materials were weighed and mixed by hand using a spatula and a small glass beaker, the Aerosil^® and magnesium stearate were shortly mixed as last additives. The slugging was done by any known means, for instance with a Korsch EK-0 excenter tabletting press equipped with flat punches of 16 mm diameter. Tablets were pressed by hand by turning the hand wheel of the press. The weight of the tablets was about 550 mg and the thickness 2 mm, the hardness was about 40 N. The slugging was followed by breaking the tablets by hand and carefully crumbling in a mortar with the aid of a pestle. The crumbled material was sieved out in order to obtain a granulate with a particle size, from 125 μm to 1000 μm, preferably from 125 to 750 μm, recycling the particles > 750 μm to the mortar and discarding the powder < 125 μm.

Dry roller compaction was done, using a IR 520 roller compactor, equipped with a Fitzmill hammer mill. The capacity is 30 to 150 kg per hour. For one full process run with optimal settings, 100 kg material was used, mixed thoroughly to homogeneity. In one batch 38 kg of Amoxycillin trihydrate was mixed with 30 kg of mannitol, 30 kg of dibasic calcium phosphate and 2 kg of magnesium stearate. In another batch 38 kg of amoxycillin trihydrate was mixed with 60 kg of mannitol and 2 kg of hydrogenated vegetable oil . In both batches the mixture was fed to the roller compactor, the compacts were milled with a Fitzmill after which a sieve fraction between 125 and 1000 μm was obtained. The compressibility index was measured by means of the following procedure. A measuring cylinder is filled with a weight amount of granulate and the volume is measured. A standardized tapping procedure is performed and again the volume is measured. The compressibility index (I) is given by the equation : I = (1 - v/v₀) x 100, where v is the volume occupied by the granulate after the tapping and v₀ is the volume before tapping. Values of I below 15 % usually give rise to good flow characteristics, but readings above 25 % indicate poor flowability (from the manual: The Theory and Practice of Industrial Pharmacy, published by Lea & Febiger, 1986) .

The pharmaceutically active material used, is an anti- infective agent selected from any of the groups of antibacterial antibiotics consisting of Cephalosporins or related β-lactams. The β-lactams are for instance penicillin V potassium salt or acid, amoxycillin trihydrate, ampicillin trihydrate and for instance Cloxacillin Sodium, Flucloxacil- lin Sodium and Dicloxacillin Sodium, and Cephalosporins are for instance Cephalosporin, Cephalexin, Cefaclor and Cefa- droxil . Furthermore Tetracyclines, for instance Tetracycline, Oxytetracycline, Doxycycline, Minocycline, Chlortetracycline and Demeclocycline or any acid salt, for instance cloric acid salt, thereof and also Macrolides, for instance Erythromycin, Clarithromycin, Roxithromycin and Azithromycin, or any stearate and/or any estolate thereof can be used to prepare the granulates of the invention.

The excipients used in co-formulation with the pharmaceutically active materials mentioned above, were selected from a group consisting of dry binders, lubricants, flow aids, taste improvers and disintegrants. A blend of several different combinations of the pharmaceutically active material and excipients was used.

Friability was monitored during filling process, trans- port and storage of the filled straw. The attrition was simulated in a so called friabilator where the granules fell over a fixed length in a flat cylinder during 100 revolutions. The weight of the granules before and after the test was determined. The colour of the granules, for instance with amoxycillin, is of some significant importance because of the used granulation process, in this case dry roller compaction. It is an indication for decomposition and loss of stability of amoxycillin during storage. The requirements for colour of the amoxycillin powder and the granulated product will be maintained throughout the process . The parameter is the so called 'colour Hunter b' ≤ 5.0 determined with a spectrocolo- rimeter .

A selection from the group of diluents and dry binder excipients used, are water soluble dry binders. These binders must ensure a reasonable friability of the active agent under standard attrition, but be wetted and admix, become in suspension or dissolve well in water to release the active agent before the admixture reaches the oral cavity of the patient. Granulates manufactured with microcrystalline cellulose such as Avicel PH102^® from FMC were used, but when they come into contact with a fluid they swell. When sipping starts fluid enters the lower part of the particle batch in the straw. It was observed that the swelling behaviour of the microcrystalline cellulose as part of a composition of the granulates or as single particles blocked further penetration of the fluid and taking the dose was impossible, also when a solubilizer such as mannitol was incorporated in the granulate. Therefor in this invention is chosen for more suitable dry binders such as dibasic calcium phosphatic anhydrous such as Emcom- press^®, which is a brand name from Edward Mendell Co Inc, mannitol in particular Pearlitol^® or sorbitol in particular Neosorb^® which are brand names from Roquette. The latter two are also known as sweeteners used to conceal the bad taste of the pharmaceutically active materials selected. Also used is a dry binder, such as Emcompress^®, in combination with mannitol .

Another excipient used is a lubricant, preferably magnesium stearate and/or a hydrogenated vegetable oil such as Lubritab^®, which is a brand name from Edward Mendell Co Inc. The granulates manufactured with this lubricant were not too hydrophobic and did not block the straw. Lubricants are used to facilitate the release of the slugged or dry roller compacted formulations from the seal-press or disks.

Another excipient used is a flow aid, preferably Aero- sil^® 200. Flow aids are used to ensure an optimal flow of the powder, during the filling process, containing the pharmaceutically active agents and excipients. The optimal flowability is tested by means of an angle of repose (from: The Theory and Practice of Industrial Pharmacy, published by Lea & Febiger, 1986) . A funnel is placed 2 cm above a plain surface, the granulate is carefully added into the funnel, adding of the granulate is stopped after the formed heap touched the funnel . The angle of repose is measured and calculated according TanΦ = 2H/D (Φ is the angle of the heap of powder, H is the height and D is the diameter) . Values of Φ are rarely less then 20°, and values of up to 40° indicate reasonable flow potential, above 50° however, the powder flows only with great difficulty, if at all.

From the group of disintegrants, the following excipients are used:

- croscarmellose sodium, which swells 4-8 times its original volume, brand names are Ac-di-Sol^® from FMC, Nymcel ZSX^® from Metsa-Serla Chemicals and Primellose^® from Avebe BA,

- crospovidone, which swells and rapidly exhibits high capillary activity and pronounced hydration capacity, such as Kollidon CL^® from BASF Pic and Polyplasdone XL^® ISP-Technologies, - low substituted hydroxypropyl cellulose,

- polacrilin potassium, as Amberlite IRP-88^® from Rohm and Haas, sodium starch glycolate, such as Explotab^® from Edward Mendell Co Inc and Primojel^® from Avebe BA. It was observed that the swelling behaviour of the disintegrants, blocked further penetration of the fluid in the straw and taking the dose was made impossible or part of the upper particle batch was entering into the oral cavity as dry particles when a disintegrant is incorporated in the granu- lates, even at low concentrations as 0,5%. Therefor in this invention as an disintegrant excipient preferably rice starch was selected. Or rice starch co- formulated with mannitol or sorbitol together with a pharmaceutically active material .

In all of the previous mentioned blends with amoxycillin trihydrate, a co-formulation with a β-lactamase inhibitor, preferably potassium clavulanate, could be used. Furthermore, in all of the previous mentioned blends with ampicillin in all of the previous mentioned blends with ampicillin trihydrate, it could be co-formulated with the β-lactamase inhibitor sulbactam.

The thus manufactured granulate is homogeneous, all excipients are thoroughly mixed before the process of granulation is started. No post granulation preparations such as addition of wax or other coatings are necessary. However filling the straw with a mixture of different complete granulates is considered, i.e. several antibacterial antibiotics combined or an additional flavour granulate added. The straws were filled with 3 cm of granules which gave an amount of 625 to 690 mg of granules, depending on their composition and physical structure.

Attention has been paid to the sticking behaviour of the material on the punch of a tabletting machine if slugging is performed and the flow behaviour characteristics of the granules in the straw when sipping is simulated. It is obviously desirable to avoid sticking to the tools as much as possible. The process which takes place in the straw, after using a Sipping Simulator on the straw placed in a fluid to enforce the fluid to by-pass the retainer, has been observed. First, the granulates should moisturize and be wetted more or less simultaneously during the ascending fluid level in the straw. Secondly, the completely wetted granulates, dissolved granulates and/or admixture rise together with the movable retainer upwards to the end of the second formulation chamber. The upper part of the particles is then approaching the second end of the straw and the admixture will finally enter the oral cavity. All this occurs without the bad taste or gritty feeling, normally associated with administering pharmaceutically active materials.

The invention is further illustrated by the following examples, which should not be considered to be a limitation of the invention. Examples

Materials and methods

I Amoxycillin and excipients

For the slugging process the following materials were used:

1. Amoxycillin trihydrate powder

2. Avicel^® PH 102 (FMC) 3. Explotab^® (Mendell, sodium starch glycolate)

4. Mannitol powder (Merck)

5. Mannitol granulate (Pearlitol^® SD 200, from Roquette)

8. Magnesium stearate

9. Aerosil^® 200 (Degussa, colloidal silicon dioxide)

Other formulations tested are:

10. DC-Sorbitol granulate (Neosorb P 20/60^®, from Roquette)

11. Rice starch

12. Emcompress^® (dibasic calcium phosphate anhydrous, from Edward Mendell Co Inc)

13. Lubritab^® (Edward Mendell Co Inc)

Also some mixtures of granules were tested (not slugged) :

14. Penicillin V Potassium (Pen-VK)

Avicel^® is a dry binder and a weak disintegrant.

Explotab^® is a strong disintegrant .

Mannitol is a cool sweetener and a dry binder.

Magnesium stearate and Lubritab^® are lubrificants for the compressing tools.

Aerosil^® is a flowing aid.

Sorbitol is a cool sweetener and a dry binder.

Rice starch is a dry binder.

Emcompress^® is a dry binder. For the mixtures also mannitol granulate and sorbitol granulate were used. II Dry granulation process

The process used to manufacture the granules is described above. Deviations from this way of preparation were that the tablets were varied in weight from 514 to 801 mg and in hardness from 9.2 to 143.2 N.

III Test of sipping behaviour using a Sipping Simulator

A Sipping Simulator is a device, designed by ALZA, to simulate the suction on the straw filled with formulations when placed in a fluid. The apparatus consists of a commercial available hand vacuum pump from Equus Products Inc. (to be used as a brake bleeding kit for cars) , a plateau fastened to the same and a tube with a valve . The tube was connected to the upper end of the straw, vacuum till 10 cm Hg was applied by hand, the valve was opened and simulated sipping started. The flow characteristics of the granulate and the fluid was visually observed.

INSTRUCTIONS FOR ASSEMBLY AND USE

The ALZA Sipping Simulator has been designed to simulate the action of drawing fluid through a straw into the mouth. The purpose is to test the functionality of Dose Sipping devices. The Sipping Simulator consists of three main pieces:

- The pre-assembled base with mounting blocks and locking pin.

- The hand operated vacuum pump with attached vacuum gauge .

- The vacuum reservoir cup.

To assemble the Sipping Simulator:

1. Remove the locking pin from the smaller mounting block by depressing the blue button and withdrawing the pin from the hole .

2. Insert the end of the vacuum pump handle (finger grips facing the hole from which the locking pin was removed) into the square hole .

3. Replace the locking pin by depressing the blue button and inserting the pin into the hole of the small mounting block.

4. Attach a piece 1/4" ID flexible tubing, approximately 20 cm in length to the outlet port of the vacuum pump.

5. Connect the vacuum reservoir lid (black, with two ports) to the vacuum reservoir. Make sure top is fastened tightly.

6. Connect the other end of the tube from step 4 to the port of the vacuum reservoir lid marked TO PUMP. 7. Insert the vacuum reservoir cup into the round hole of the remaining mounting block.

8. Place a roller clamp over a second length of tubing, approximately 28 cm in length, and attach the tube to the remaining port of the vacuum reservoir lid.

To use the Sipping Simulator:

1. Using the roller clamp, completely pinch off the tubing from Step #8 previous. 2. Actuate the hand operated vacuum pump until the gauge reads 10 cm Hg vac on the inner scale, or 4 inch Hg vac on the outer scale.

3. Remove the cap from a Dose Sipping device and insert the now exposed tapered end into the flexible tube. 4. Place the opposite end of the Dose Sipping device into a container of fluid. Use a container that is not easily tipped over to prevent spillage.

5. Release the roller clamp. If the granules all exit the end of the straw, and the plug is at the exit orifice, then the Dose Sipping device has functioned properly. The granules need not all enter the vacuum reservoir cup. If the granules do not exit the end of the straw immediately, maintain a maximum of 10 cm Hg vac (4 inch Hg vac) for 2-3 seconds by pumping the vacuum pump. If the granules are still at the end of the straw and have not properly cleared the orifice, the physical behaviour of the granules is incompatible with the functioning of the Dose Sipping device and consequently has failed to function properly.

6. Reset the roller clamp, and disconnect the Dose Sipping device. Release the roller clamp and clear all tubing and the vacuum reservoir cup of fluid and granules as needed. Do not allow fluid level to reach the top of the vacuum reservoir cup.

The procedure for the Sipping Simulator was as follows:

1. About 650 mg of granules of the formulations mentioned above, were put in a straw also described above.

2. The upper part of the straw was attached to the tube of the Sipping Simulator which was preset on a pressure of 10 cm Hg and the lower part in distilled water.

3. The pressure was released by opening the tube clamp and the behaviour of the granules was observed.

The straws were filled with 3 cm of granules which gave an amount of 625 to 690 mg of granules, depending on their composition.

Formulations

Compositions of granulates made by slugging are shown below

Properties of the granules

The properties of the tablets and granules are given in the following table.

B Formulations

Compositions of granulates made by slugging are shown below

The following mixtures of granules (not slugged) were also tested in the Sipping Simulator.

Properties of the granules

The properties of the tablets and granules are given in the following table.

A3 to E3 series

The tablets often stuck to the punch. The tablets of A came mostly crumbled out of the press, whereas the tablets of B, C, D and E (which contained Emcompress^®) broke often horizontally. Formulations containing the binder Emcompress^® showed less crumbling, the sticking behaviour stayed the same.

F3 series

The F tablets containing 2% magnesium stearate gave no problems making the tablets : the tablets did not crumble or break and did not stick to the punch. G3 to K3 series

The tablets stuck a little to the punch and very few tablets capped or broke. This was the positive influence of the lubrificants magnesium stearate and Lubritab^®. Magnesium stearate worked slightly better as a lubrificant than Lubritab^® if looked at the difference in tablet behaviour between F and G (both containing 2% of lubrificant) .

L3 to 03 series The M3 to N3 tablets with sorbitol stuck much less on the punch than the tablets with mannitol (L3 and 03 ) . A disadvantage of sorbitol is that it is hygroscopic, mannitol is not. A formulation with only rice starch and amoxycillin, M3 , gave however tablets that did not break or crumble.

Test of sipping behaviour using the Sipping Simulator

The granulates made from all described powder mixtures were tested in the Sipping Simulator.

Granules made by slugging

The behaviour of the granules from the batches C2 to H2 and A3 to T3 with the Sipping Simulator is shortly described in the following tables.

Results C2 to H2 series

Results A3 to T3 series

A3 flows slowly (± 0.5 - 1 second)

B3 slows slowly (± 0.5 - 1 second)

C3 flows slowly (± 0.5 - 1 second)

D3 flows slowly (± 0.5 - 1 second)

E3 flows slowly (± 1 second)

F3 flows slowly (± 1 second)

G3 flows well

H3 flows well

13 flows well

J3 flows well

K3 flows well

L3 flows well

M3 flows slowly (± 1 -2 seconds)

T3 flows slowly (± 2 -3 seconds)

Results sieve fractions of dry granulated amoxycillin

For none of the formulations blocking of the straw was seen.

The behaviour of the granules looked all quite similar.

First there was a small dry part at the top of the straw and a larger part in suspension below this dry part. Then after about 0.5 to 3 seconds the dry part also came in suspension and the suspension as a whole flowed out of the straw. The difference in flow velocity was approximate: because of the fastness of the process it could not be noticed very well. It was sometimes necessary to use extra sucking pressure for granules that flowed slowly.

II Other granules : mixtures of granules and commercial formulations

Results Pen-VK and N3 to S3

Pen-VK flows slowly (± 1 second)

Pen-VK, sieved fraction of flows slowly (± 0.5 second) 250 to 1000 μm

N3 flows slowly (± 2 seconds)

03 flows well

R3 flows well

S3 flows well

The solubility of Pen-VK was good and the granules dissolved when the sucking experiment took place. When tested with the mouth Pen-VK gave a very bitter taste and suspension and/or solution in the mouth, so dry granulate entering the mouth must be avoided.

The formulations with a lubrificant as added excipient stuck less on the tabletting punches and gave tablets that crumbled and capped less .

Formulations with sorbitol stuck much less on the punch than formulations with mannitol. A disadvantage of sorbitol is that it is hygroscopic, mannitol is not.

The mixtures of granules made with amoxycillin trihydrate compacted were very static, this might cause separation of the mixture and will give serious trouble during industrial filling processes.

Claims

1. Homogeneous granulated formulations, with a particle size from 125 to 1000 μm, whereby each particle comprises a blend of one or more pharmaceutically active materials and one or more excipients.

2. Formulations according to claim 1 with a particle size from 125 to 750 μm.

3. Formulations according to claim 1 or 2 wherein the pharmaceutically active material is an anti-infective agent, preferably an antibiotic.

4. Formulations according to claim 2 or 3 wherein the antibiotic is Penicillin, for instance penicillin V potassium or amoxycillin trihydrate, or Cephalosporin, for instance Cephalexin.

5. Formulations according to any one of the claims 1 to 4 wherein the pharmaceutically active material is co-formulated with a water soluble dry binder, preferably mannitol and/or sorbitol .

6. Formulations according to any one of the claims 1 to 5 wherein one or two of the excipients are a lubricant, preferably magnesium stearate and/or Lubritab^®.

7. Formulations according to any one of the claims 1 to 5 wherein one or two of the excipients is a dry binder, preferably Emcompress^®.

8. Formulations according to any one of the claims 1 to 5 wherein two of the excipients are Emcompress^® and magnesium stearate.

9. Formulations according to any one of the claims 1 to 4 wherein one of the excipients is a flow aid, preferably Aerosil^® 200.

10. Formulations according to any one claim 1 to 3 wherein one of the excipients is a disintegrant, preferably rice starch.

11. Formulations according to claim 4 wherein the pharmaceutically active material is amoxycillin trihydrate, co-formu- lated with rice starch.

12. Formulations according to any one of the claims 1 to 11 wherein one of the pharmaceutically active materials is a β- lactamase inhibitor, preferably potassium clavulanate.

13. Formulations as described in claims 1 to 11 wherein the pharmaceutically active material, selected from the group consisting of Penicillins, is preferably penicillin V potassium, ampicillin trihydrate or ampicillin trihydrate co- formulated with the β-lactamase inhibitor sulbactam.

14. Formulations according to any one of the claims 2 to 10 wherein the antibiotic selected from the group consisting of the Macrolides is preferably Erythromycin, Erythromycin stearate and/or Erythromycin estolate.

15. A process to manufacture homogeneous granulated formulations as defined in any one of the claims 1 to 14, characterized by wet granulation and further sieving of said blend.

16. A process to manufacture homogeneous granulated formulations as defined in any one of the claims 1 to 14, characterized by dry granulation such as slugging and/or dry roller compaction and further breaking and sieving of said blend.

17. Formulations as described in any one of the claims 1 to 16, to be used mixed with separate granules consisting of excipients .

18. Use of formulations as described in any one of the claims 1 to 17, suitable for oral delivery, preferably by means of a Dose Sipping device, comprising a formulation chamber, having a first end and a second end, containing said formulation and a retainer for preventing release of said formulation from the first end but permitting fluid entry into the chamber.