SA08290670B1 - Manufacturing Process for a Pharmaceutical Sodium Picosulphate Product - Google Patents

Abstract

Abstract: The invention relates to a process for preparing a pharmaceutical composition comprising a homogeneous or substantially homogeneous mixture of citric acid, magnesium oxide, potassium bicarbonate and sodium picosulphate, optionally orange flavoring and/or saccharin sodium, intermediates and products. Figure (1).

Description

Manufacturing process for a pharmaceutical sodium picosulphate product. full description

Invention background

The present invention relates to an improved process for the manufacture of a pharmaceutical product” as well as products and intermediates therefrom. pharmaceutical product used to empty the bowel prior to oS-ray examination (laparoscopy or surgery); © Wa is sold under the trademark PICOLAXTM The pharmaceutical product is a white powder which is made as a solution (in water) for administration. The required properties are that it is a strong laxative and easily palatable. The pharmaceutical product contains sodium picosulphate “(ps) citric acid “stimulant laxative anhydrous” magnesium oxide 5 (CA) “(<add MgO) as they are together in the form of a magnesium citrate solution It is considered an osmotic laxative that has 0 strong laxative effect.

The oral dosage form is in the form of granules. The term granule(s) here includes loose particles (such as particles collectively called powder; including loose particles in powder form known in this field as Goad for administration by (add) the product is anh mixture of six Raw materials are citric acid (such as citric acid not we 0 or magnesium oxide Ji) magnesium oxide light citric acid monohydrate); saccharin sodium «NaPIC sodium picosulphate «((KHCO3) potassium bicarbonate « and orange flavor, magnesium oxide . orange flavour "light" here means magnesium oxide ‎YYye

a

It has an apparent volume whereby the mass occupies 15 g leas between VO and 0181 ml; eg running

Mass Vo is g in volume 816 aly ml.

The process known to do 0100187714 can contain the following steps. granules are produced

magnesium oxide citric lighter by mixing the two chemical agents together - this is known as "the mixture

5 initial. at another stage; elas sodium picosulphate « potassium bicarbonate or

They are blended to produce a wet “pre-mix” which is then dried.

Flavoring ingredients » sodium saccharin y orange flavour ¢ with premix

and the initial mixture. The well-known process is accompanied by many different problems.

 Mixing processes can lead to  Jia problems of heterogeneity in the final 0 products and intermediates. in one of the features; The expressions 'heterogeneity' and 'lack of homogeneity' refer as used

This application indicates a lack of uniformity of the content of the active ingredient - sodium picosulphate - in the product

final, for example. Lad indicates a lack of homogeneity in physical and morphological properties; Jie

The particle size (diameter), range or particle size distribution of intermediate and/or granular products

final. The “intermediate product” granules are, for example, premixed granules or Vo premixed granules.

The homogenizing agent is expected to be at least one of the critical factors ensuring quality and performance

finished product; It is believed that product homogeneity (and heterogeneity) relates to the mixing processes used. Subsequently;

In the first stage of the known process; Variations in particle size and distribution (ie

Increased heterogeneity) due to poor binding or agglomerating properties between particles of citric acid & magnesium oxides 0 (resulting for example from the difference between the densities of the two materials). Furthermore

‎YYye

(sll) Magnesium oxide lags on the mixer tray; blades, etc. (other than when mixed

With JU (citric acid) in the known process; additional magnesium oxide is included

(excess") in the raw materials to compensate for the loss during the mixing process. The excess is typically higher than .701.

This leads to economic loss in longer periods and when producing larger quantities. additionally; 0 process requires longer processing times; Incorrect amounts of dust are produced during mixing.

in the pre-mixing stage; Lack of homogeneity can appear in the resulting granules as a result of dissolving some

(smashing) in the medium of granulation; water; and due to physical decomposition (smashing) potassium bicarbonate

to particles during mixing. This can have a detrimental effect on the final product. Furthermore it; obliges

long dallas times; many steps; This is to complete that step with Allg (4 yo pattern takes 0 to YE hours).

General description of the invention

The present applicants have developed a process by which all problems in the art process can be addressed

previous; For example, current demand provides an improved product and/or significant reduction in processing time. Thus ye 3 is carried out in accordance with the ye features 1 of the present invention 3 providing a process for preparing a septic compound that includes

on a homogeneous or substantially homogeneous mixture of potassium « magnesium oxide » citric acid

sodium picosulphate s bicarbonate «and optionally» saccharin sodium and/or orange flavor

orange flavor ¢ includes:

¢ magnesium oxide s citric acid J Dry mix (0

(b) applying by spraying (eg Je) a solution of sodium picosulphate onto potassium bicarbonate ¢ and drying said potassium bicarbonate 5 sodium picosulphate; and (c) mixing at least a portion of the product of step (1) with at least a portion of the product of step (b); optionally saccharin sodium and/or orange flavor. Other (d) To mix the product from step (c) with another quantity of the dry-mixing mixture of magnesium oxides citric acid [eg some or all of the remaining product of the process specified in step] ¢ and/or a spraying-formed product (Mia a solution of sodium picosulphate on potassium bicarbonate and drying sodium el potassium bicarbonate 5 picosulphate eg JE some or all of the remaining product of process 0 specified in step b)]. One feature is to provide a process for preparing a pharmaceutical composition comprising a homogeneous or substantially homogeneous mixture of potassium bicarbonate ¢ magnesium oxide ¢ citric acid, sodium picosulphate ¢ and optionally saccharin sodium and/or orange flavoring flavour ¢ comprising: Jalal (9) dry yo of magnesium oxide 5 citric acid ¢ (b) applying (for example by spraying) a solution of sodium picosulphate on potassium bicarbonate » and drying sodium picosulphate and potassium bicarbonate mentioned; and (c) mix at least a portion of the product of Step A with at least a portion of the product of Step B; and optionally saccharin sodium and/or orange flavour, and Yo (d) mixing the product from step (c) with all or part of the remaining product by the process specified in step

(a); and/or some or all of the remaining product of the process specified in step (b). the resulting homogeneous or substantially homogeneous mixture of magnesium oxide “citric acid ¢ potassium bicarbonate” and sodium picosulphate; Optionally, sodium saccharin and/or orange flavor may be in the form of granules. The granule (granules) can have a range or a particular size distribution (diameter) between about 001 and about 000 SSeS for example between about 151 and 475 µm; For example between about You and about +85 µm. The pharmaceutical composition may be in the form of granules having a range or particle size (diameter) distribution between about 0 and about 900 μm. For example between about 1510 and 4925 µm” eg between about Yoo and about 0 88 µm. Ye In this document it must be understood that the expression diameter does not mean that any of the detected particles and granules are spherical. As shown in the attached figures; The granules can, for example, be roughly spherical; in the form of elongated pellets (oval shape) and so on. Herein the expression means the size (diameter) of the shortest distance in a straight line passing from one side to the other through the center point of the particle (eg 8S is a sphere i is an elongated sphere; Ve is an oval). Tie of the present invention; In another aspect, a granule, granules, or pharmaceutical formulation is provided; Comprising a homogeneous or substantially homogeneous mixture of a homogeneous or substantially homogeneous mixture of citric: 1 sodium picosulphate 5 potassium bicarbonate “magnesium oxide” acid and optionally; saccharin sodium » and orange flavor. Pharmaceutical Composition 0 of the present invention may be used to empty the bowel prior to examination with x-ray, laparoscopy or surgery. maybe

The granule(s) have a particle size (diameter) range or distribution between about 100 and about Too µm; for example between about 151 and 8785 µm; For example between about YO and about 0 05 µm. Said granule(s) or pharmaceutical composition may be distributed in sachets. © Consistency of the content of the active substance. sodium picosulphate ¢ in the final product granule(s) or in

A pharmaceutical composition can have a mean value of about 70.0884 to Te tA by weight 11-9 (mg/dose; based on a dose of 16.1 g 010014<714). According to the present invention and in the feature of cg Al a pharmaceutical preparation or pharmaceutical composition comprising granules is provided a product of a homogeneous or substantially homogeneous mixture of a composition comprising granules

Ve (primary) of magnesium oxides citric acid as described Je) for example include granules containing “magnesium oxide 5 citric acid” and the granules include a layer of magnesium oxide encapsulating a core of citric acid ); and a second composition comprising granules (sec) of WS sodium picosulphate 5 potassium bicarbonate described herein Je) e.g. comprising granules comprising potassium bicarbonate s sodium picosulphate ¢ and comprising

0 granules on a layer of sodium picosulphate coated to a core of ¢ (potassium bicarbonate) and optionally saccharin sodium and/or orange flavor 0 orange flavour. The resulting granule(s) can have a particle size (diameter) range between Approx. 001 and about 000 µm. The resulting granule(s) may have a consistency of sodium picosulphate content of an average value between about 0.05 and 1A.02 by weight. The process of the invention may include a potassium bicarbonate separation step or steps For example to get (ie for example sieving le)

of adequate size and/or volumetric distribution - for example; particle size (diameter) range; For example; between about 001 and about 900 micrometers; For example between about 156 and 8785 µm. eg between about +75 and about +45 µm prior to application (by spraying

spraying © for example). The process of the invention may contain a separation step or steps (sieving (Sie) for example to obtain citric acid of an appropriate size and/or size distribution; for example a range of particle size, for example JEN between approx. 001 to approx

0 μm; For example between about AVE 1500 μm; eg between

approx. Yoo and approx. 0 85 µm = before mixing with 0 magnesium oxide

Yes The present invention provides dle Lad for the preparation of a pharmaceutical composition comprising a homogeneous or substantially homogeneous mixture of potassium bicarbonate ¢ magnesium oxide 6 citric acid sodium picosulphate and optionally saccharin sodium and/or orange flavoring flavor (and/or a process for preparing a composition comprising magnesium oxides citric acid (¢ incorporating

On the dry mixing step of citric acid with magnesium oxide (eg magnesium

light oxide VO); Using a means to form a homogeneous mixture of compounds of significantly different densities (Jia (multidimensional mixer or three-dimensional mixer). The device can mix using a three-dimensional movement (Je) eg the well-known aul principle (Paul Schatz The tool ela) can mix using a three-dimensional movement lly comprising a form of A movements with rotation; which leads to movement

The materials inside the mixer are in a regular pulsating motion. The method can promote Adee intercitric agglomeration

multi-dimension Mi) The device can be locked. magnesium oxides 0

blender or three-dimensional blender during dala which may prevent dust or contaminants. The medium (eg a three-dimensional mixer or mixer) may mix by the effect of shaking or motion of the mixing bowl (eg swirling motion) with triple cal motion) as well as by the use of a blade or stirrer inside the bowl (As in a conventional planetary blender © 0. J) 3D motion can prevent particle damage (and inconsistent product size) associated with conventional mixing techniques – for example, caused by frictional forces between the blade or the agitator paddle and mixing vessel side -mixing vessel side citric acid may for example be loaded in one batch into the medium to form a homogeneous or substantially homogeneous mixture of compounds of substantially different densities (Jie) multi-dimensional mixer or 0 Mixer 3D); before adding magnesium oxide. Magnesium oxide eg JE may be added in a number of batches from * to + eg ay mixing the addition of each class with another. Adding MgO in small batches to the total amount of citric acidd and mixing each batch addition with “MgO Adee can enhance agglomeration among magnesium oxides citric acid” and/or homogenize the resulting Ve mixture and/or or reduction of MgO loss The process may contain a separation step or steps (eg by sieving Jail) to obtain citric acid of an appropriate size or size distribution - eg a particle size (diameter) range; for example between about 001 and about 900 µm for example between about AYO 151 µm; For example between about You and about Ale μm - Yo before mixing with magnesium oxide . The process optionally includes one or more steps of a separation (eg sieving) in order to obtain, for example, a resulting composition/particles of an appropriate size (diameter) and/or size distribution. (diameter) particle and/or Particle size (diameter) distribution ana The formulation/particles (the resultant) Ka should be consistent with the particle size or particle size distribution of the pre-mixing or with the application (by spraying and then drying) step. (yey potassium bicarbonate on sodium picosulphate (ic spraying considered to be agglomerated particles) of Ally according to another feature of the invention; granules (eg

Too and about 1001; It has a particle size distribution range of about magnesium oxide 5 citric acid

Micrometers eg between about AVE 1510 µm; For example between micrometres. The particles can have a particle size (diameter) distribution of more than 850 and about 7960 eg more than 797 particles having a SET OED #water eg 0 and about 00 μm; For example; Between about 100 particle size (diameter) between about μm. and can as and about you micrometers; For example between about AVE and about 0 the particles have a particle size distribution (Diameter) of less than 75; for example less than 8500"; for example less than 77 of the particles having a particle size (diameter) greater than about for example less than IY μm and/or where less than eg less than 75 From 0 µm You can be particulate matter having a particle size (diameter) less than about 1 in 725, ie less than 77 on a JB of particles having a particle size (diameter) distribution where the μm; AVE of particles having a particle size (diameter) greater than about 71 eg less than eg less than 71 eg JY JB eg do be less than Gua and/or µm. The granules can have a particle distribution of 151 having a particle size (diameter) less than about Yo

- 11

JE less than 77 for example JB particle size (diameter) where less than 70 is for example less than 779 particles having a particle size (diameter) greater than 900 µm; and/or where the particles have eg 71 less than JY than 0 eg less than J µm. The granules can have hook size (diameter) 001 particle size (diameter) less than approx.

Yoo and about 900; for example between about 0.1 JO particle eg µm. AO and about 750 eg between about lag Sue AVS can be for grain size or consistent particle size distribution With mixing with the product from the step of applying (by spraying and drying) potassium bicarbonate on sodium picosulphate a solution of (Mie spraying) potassium bicarbonate 5 sodium picosulphate . citric acid can contain J Suspension of magnesium oxide granules on a layer of 0 citric acid According to another feature of the invention; a composition comprising granules containing “citric acid coated to a core of magnesium oxide – the granules comprising a layer of magnesium oxide is provided For example Shag Sie 15 A value ranging from * to magnesium oxide The thickness of the aly layer can be μm The granules can be a width between 4860 and 8080 01 eg from 0 to eg a width between 500 and 1700 µm) at a point of greatest width [i.e., Jo) µm VO over the longest distance in a straight line passing from one side of the particle to the other through the center point of the particle (for example, a rough sphere; In another aspect, the present invention provides a process for preparing a pharmaceutical composition comprising a homogeneous mixture of potassium bicarbonate ¢ magnesium oxide « citric acid or a substantially homogeneous mixture of orange jill and/or a flavoring of sodium saccharin and optionally » sodium picosulfate 5 0

Cy sodium 5 potassium bicarbonate (and/or a process for preparing a composition comprising “flavor sodium” a solution of “Mie spraying” comprising the step of applying (spraying) potassium picosulphate and sodium picosulphate and drying ¢ potassium bicarbonate on picosulphate .bicarbonate eg between Jeo apn size range (diameter) potassium bicarbonate µm for AVEO could be about 150 and about 900 µm; for example between about 100 µm about μm The process can have a step of AO and about Yoo for example between about an size of potassium bicarbonate or separation steps (eg by sieving); for example to get particulate; for example between (Lhd) or an appropriate size distribution - eg; AYO size range of approx. 151 µm and approx 100 µm; eg between approx. 001 Ve approx 450 µm and approx. You can for example between about In the form of an aqueous solution The weight ratio between sodium picosulphate can be 1:1 and 1, for example between 1:1 oF and 1:1 and water In the solution between sodium picosulphate sodium picosulphate a solution of 1:7 and 1,5:1 5,”,; For example between about

Aids [de Yo] to 1 at a rate of Se spraying e.g. aqueous solution (V0 - 11 to 01 ml/min.) with an aqueous solution. The solution can be applied; e.g. sodium picosulphate in one example is potassium eg an aqueous solution (eg by spraying) on a surface eg granules or particles ;!1"1

1 = bicarbonate . The solution oJ can be applied for example in aqueous solution 5 J _ (die spraying) as fine liquid droplets for example. Potassium bicarbonate can be preheated (for example before application) by spraying (lie of a solution of sodium picosulphate on Je ( potassium bicarbonate eg; to a temperature between eg a Te and 1000 ºC from eg 70 ºC to Ve µm; eg 70 ºC to - ºC. Can be dried sodium picosulphate and potassium bicarbonate at a temperature for example between 17°C and 100°C, for example from 70°C to Ve°C, for example from 70°C to 20°C, for example ©4 C. Drying can be done using [eg blowing mode] warm or hot air (eg at a temperature between 0°C and 1000°C; 0 as <1°C to a Ve and as 70°C to 0 + m) Drying can be during application (eg by spraying); and/or immediately or substantially after application (by spraying) There can be one or more application methods (eg oF oY JU one or more methods of application () by spraying (Sie) of a solution of sodium picosulphate «sodium picosulphate» and potassium bicarbonate which are dried during or directly or to a large extent after each application (by spraying). VO Application (eg spraying) and drying can be done eg in an inverter coating machine; Or another coating machine (eg liquid coating machine) known to those with experience in the art. The application by spraying (Die) and drying of sodium picosulphate and potassium bicarbonate can thus be completed in one step using the same Yay coating machine without the need for two or more separate steps (planing; drying); and and/or two or more separate machines.

“ye The process can be self-controlled. Thus, manual processes can be avoided; Again allowing for a reduction in the overall process time. The process can contain a separation step or steps (eg by sieving) to obtain a product of suitable size and/or size distribution - eg; particle size (diameter) range; For example from 4975 to about 150 to about 300 micrometers; ie from about 001 about 5 to about +45 µm. 720 µm; For example of about sodium picosulphate and potassium bicarbonate the composition comprising (the result) may have a particle size (diameter) and/or a particle size (diameter) distribution that corresponds to the particle size or ‎ citric acid The particle size distribution of the initial mixture or product from the dry mixing step of potassium bicarbonate for the (product) composition comprising . magnesium e.g. 0 of 7957 particles SST has a particle size (diameter) distribution where sodium picosulphate and eg between about flag Sue 900 and about 0 have a particle size (diameter) Between about and about 850 µm. You could for example be between about “jing Sue and 8750 0 The distribution of sodium picosulphate 5 potassium bicarbonate The (result) composition containing eg is less than 77; eg 12 particle size (diameter) being less than 15 0 µm; and/or where 0 particles have a particle size (diameter) greater than about 1 less than 0 particles have a size of eg 71 less than ZY than eg 75 less than Ji potassium micrometer. A composition containing YO particle diameter less than about 75 on dil has a particle size distribution where sodium picosulphate and bicarbonate are particulate matter having a particle size 71 eg is less than AY eg is less than ys

0

larger than about AVE µm; and/or where it is less than 25; eg less than AY eg less than 71 particles have a particle size (diameter) less than 1051 µm. A composition comprising sodium picosulphate 5 potassium bicarbonate may have a particle size (diameter) distribution of less than 75; eg less than 77; © for example less than 71 of the particles have a particle size (diameter) greater than about 000 µm; and/or where the oF is eg less than 77; For example less than 71 of the particles have a particle size (diameter) less than about 100 µm. The (result) composition comprising potassium bicarbonate and sodium picosulphate may have a body size (diameter) range or distribution; For example J is between about 001 and about 900 μm; For example

Ve is between 151 dla and 8775 µm eg between about Yoo and about 0 45 µm. The formed product or composition by applying (Sie spraying) a solution of sodium picosulphate on potassium bicarbonate and drying can be in the form of granules or particles; to it according to the present invention in the coal feature a composition including granules containing Sodium phosphate 0 Potassium bicarbonate s ¢ The granules include a layer of sodium picosulphate encapsulated to the core Potassium bicarbonate The granules can be, for example, largely oval [eg (JE) in the form of an elongated ball (See eg fig. ?).] The grains can be substantially elliptical in which the shortest dimension is in the straight line passing from one side of the grain to the other through the center point of the grain between 001 Vo and.. μm (eg 70060 to 400 μm); and/or the longest dimension is in

Ce The straight line passing from one side(s) of a particle to the other through the center point of the particle between µm (Vou to 0 0 e.g. Jo) and 40 µm © sodium picosulphate J Premixed granules another ds of the invention; .aad is based on Veo and approximately 100 particle size (diameter) bands or distributions between approximately » potassium bicarbonate μm; For example between about AVE to 151 between about JE µm; eg © 0 48 µm and about Yon sodium picosulphate according to another feature of the invention; Provides a granule or granules that include a layer. The granules can have a particle size (diameter) distribution as the . potassium bicarbonate over eg over 7950 eg over 797 TAS particles over between about JE μm; For example 000 and about 001 have a particle size (diameter) between about Ve z μm. 850 and about You can for example between about «lag Se AVE; 00

AY less than JE The granules have a particle size (diameter) distribution of less than 25; For example

Aor eg less than 779 particles having a particle size (diameter) greater than about eg less than IY μm; and/or where less than 75; For example, less than a micrometer. You can be of particles having a particle size (diameter) less than about 29 1 on the AY for particles having a particle size (diameter) distribution of less than 725; For example less than µm AVE sa of particles having a particle size (diameter) greater than 71 eg less than eg less than 71 of XY and/or where less than 75 ; For example, less than a micrometer. The granules can have a distribution of 151 particles having a particle size (diameter) less than about eg less than ZY less than JU particle size (diameter) less than 75 for example Yo

1 µm; and/or where 000 of the particles have a particle size (diameter) greater than about 71 of the particles have eg 71 of 75 less than eg 77 less than J µm. The granules can have a size (diameter) range of 0.100 particle size (diameter) less than about 151 and about 00 μm; For example between 1001 particles; For example between about µm. AS and about Yoo can be µm; For example between about AVE, 5 sodium picosulphate to the granules of the premix produced by the methods of the present invention a uniformity content of the Jal composition (mg dose) which contributes to the homogeneity of the final product. The invention may provide in “sodium picosulphatc and potassium bicarbonate” an intermediate or premix comprising (dose mg) which is consistent with “sodium picosulphate as granules” and which has a determinant of regularity that of a granule ( granules) finished product or pharmaceutical formulation (see above) and a size range of 0

Vou and about 00 μm; For example between about 100 (diameter) particles between about 0 85 µm and about Yoo 0 µm.; For example between about AYO iy with steps (a), (b), (c) etc; Led) It must be understood that the process steps here can be referred to for clarification only; There are no requirements for clarification or inclusion regarding the order of steps. Subsequently; The step (a) process can be completed before; After or at the same time to a large extent by step JE dpe 0 (b). A brief h of the drawings or citric acid of a granule of an initial mixture of EDAX and the results of the SEM analysis showing pictures (Fig. 1): (1).

VA - - The mentioned pictures show that MgO is present on the outer shell of the granule. Photo J black and white (electronic image 1) shows a nearly spherical pellet which is cut at a plane to show the pellet core and coating. The other picture (1-2) (Mgka) shows the position of the element Mg (more common / whiter dots). By comparing the two pictures, it is clear from the section that the core of the particle has a very small element MgO© (and the small amount is the result of contamination during cutting the sample In the preparation process of (EDAX) while the coating contains a large amount of MgO. The total spectrum shows the total element MgO on the surface of the particle (section and coating). In addition to (Sl) the black and white image clearly shows that the particle has a crystalline core From citric acid and a white coating of MgO Ve, the thickness of the MgO coating layer can be calculated from the black and white image (Je (JE path) using a ruler) to be ©-01 μm. It shows the SEM images and the results of the EDAX analysis of a granule of a premix of sodium picosulphate potassium bicarbonate 5 according to one of the models of the invention; it was taken by the example method (1). It is clearly detected on the shell 0 and the element K (i.e. (potassium bicarbonate) is clearly detected on the core. The black and white image (electronic image 1) shows a premixed granule lly cut to show the core and the shell of the granule. The photo shows Skal The position of element 5 on the pellet (dots). It is clear that most of element 8 occupies the shell; The small amount of element 5 at the level of the section iat in contamination due to the cutting process in dee Sample preparation for EDAX The picture shows K Kal

1 2 _ — position of an element on/in the granule (dots); It can be seen that the section plane (the core of the pellet) has more elements than the casing. SKal 5 K Kal proves that the coating contains both elements K Sy which indicates that the sodium picosulphate layer is very thin (because its quantity is low Jas - only 77 according to this formulation of the premix). : © The black-and-white image clearly shows that the grain has a (crystalline) core of potassium bicarbonate and a (white) shell of sodium picosulphate. The granule can be described as a largely elliptical body. The detailed description of the present invention will be clarified by reference to the following examples and the attached figures, which led to Figure (1) showing the SEM images and the results of the EDAX analysis of granules of an initial mixture of magnesium oxides citric acid 0 according to the invention model;

Figure (1) shows the SEM images and the results of the EDAX analysis of granules of a premix of 010050101846 sodium 5m potassium bicarbonate according to the sample of the invention.

The product PICOLAXTM is a physical mixture of six raw materials; This could be citric

‎sodium «(KHCO3) potassium bicarbonate « magnesium oxide ‎(not matte)‎ acid

,. orange flavor and orange flavor » saccharin sodium » picosulphate 0

In the first phase of the known process of action of PICOLAXTM as discussed above; jumble

The first one, which includes magnesium oxide and 2610 citric, must first be produced. J who lasts

Additional magnesium oxide ("reserve") is measured as part of the feed to replace losses during the process

mixing. YYye

1.0 It is then mixed or mixed with eles sodium picosulphate » potassium bicarbonate in the second stage

J! 3 1] to produce L. Then the pre-mixing granule is dried. in the third stage. flavor components; orange zest and then blend it with the premix and the initial mixture. ¢ saccharin sodium; and orange flavor according to the present invention; in some features; The process also requires several different stages. © : the initial mixture in the prior art process; I found discrepancies in particle size and distribution, apparently as a result of the properties of the art equipment. magnesium oxide and citric acid particles with poor binding or agglomerating properties between oe xa . in an OL displacement mixer | Planetary Dry 1 J FE ¥ Ex 1 Serving which m magnesium on the separation of the two components and also the loss of raw material in the form of 38 (eg Ye. oxide magnesium) using the known process; it is necessary to replace the loss on a regular basis by adding which leads to an economic loss of an additional 700 (excess") in an amount typically greater than oxide necessitates long processing times; long nitrate quantities can be produced and larger quantities produced. Vo in the form of MgO during mixing. MgO undesirable by-pass of the prior art process can lead to cleaning difficulties; and/or poor control of the granular/particle size and distribution produced.” magnesium oxide 5 (YA) citric acid stage or step of the present invention includes dry mixing for "<<

— \ a _ to produce the "initial mixture". Unlike the previous art process; A better lumpy mixture can be obtained by mixing citric acid & magnesium oxide using a multi-dimensional mixer or a SoS dimensional mixer. The surplus is significantly less. Three-dimensional mixers are known and can be obtained for example from Laval Lab Inc, of the US ©. The mixing bowl is moved using a three-dimensional motion (known as a Panl asa (Schatz) which includes a model of / motions with rotation Which leads to the movement of the material inside the mixer in a uniform and pulsating manner.This movement can mix powders and granules of different weights, sizes and flow properties.The multi-dimensional mixer uses strong physical force in the absence of blade to mix materials as well as the mechanical agitator (as in a planetary dry mixer). This can reduce particle damage (and non-guid product size) caused by frictional forces between the stirring blade or stirrer and the side of the mixing vessel. This also reduces particle damage which is thought to affect the homogeneity of the final product; and/or sticking to the inner wall of the mixing bowl.Moreover, cleaning is easier because there is only a smooth inner surface to be cleaned (Y) 0 there is a stirring stirrer for cleaning.The use of a multi-dimensional mixer or a three-dimensional mixer is accompanied by pressure appropriate to the operating parameters » Rotational speed » Mixing time and frequency of adding the material Thus, in the process, the problems encountered in the previous art process are removed or to a large extent reduced. Pre-mixing: in the second stage of the previous operations; when producing the premix; sodium picosulphate was mixed

1 potassium part of cada ll dissolved while mixing potassium bicarbonate in a wet state with part pulverized by means of a stirring paddle; These actions resulted in the presence of Aig + bicarbonate powder in the premix after drying. I think the homogeneity of the product; potassium bicarbonate flour plus Jil sodium picosulphate from that; Because the coating of large particles or granules contains Sb in an amount of sodium picosulphate while the coating of fine particles or granules with the dry mixture contains very large ©; He believed that these extreme values affected the uniformity of the product. The well-known process also requires drying the wet mixture for a long time. The known process may require several different manual steps with risks of product contamination and increased safety requirements for the operator. spraying The method contains a placement step (by spraying Mall according to one or more features of the invention sodium and drying » potassium bicarbonate on sodium picosulphate liquid from (Die Ve 0 potassium bicarbonate 5 picosulphate mixing/coating process cha) This mixing process is thought to be similar to the coating process. For example, the exact fit to the operating parameters can be done using a machine Displacement coating its work to control the level of coating. On sodium picosulphate J (Mann's solution) JEN the solution can be sprayed (eg the mentioned Jay 0 potassium bicarbonate and drying sodium picosulphate (Sass csodium bicarbonate (i.e. coated premix granules) in the same equipment This can lead to a significantly reduced production time of sodium picosulphate eg “premix” can be produced from an hour using the YE process to 15 in about ¥ hours [in addition to potassium bicarbonate prior art].

YYyye

- a

Furthermore it; The applicants found that there could be a clear reduction in heterogeneity in

product granules; As follows, 0. Sodium picosulphate solution can be sprayed very uniformly on a surface

KHCO3 granules and drying it immediately after application (by spraying, for example); quantity can be reduced

The fine powder. Jag is the potential for grain reduction during; For example ¢ crushing of particles/© granules during the coating process. In addition to ells because the coated granules can be dried instantaneously or instantaneously

to aa large eg JE with warm air” flour and spare parts; It can fade away

Clear.

orange flavoring ¢ saccharin sodium, the process of the invention may include mixing lly

flavor + part of the initial mixture and premix; in a subsequent combination with the remainder of the initial mixture 0 (and mixing) to provide the final homogeneous mass product. '

Then the disclosed invention could provide a clear improvement in one, two or three ways

One of the steps of dle is mixing. More efficient operation can be provided; It is characterized by improved quality and productivity (Slo).

For example, for the uniformity of the active substance). A method can be provided with little risk of contamination and/or loss

metal and/or with less manual operation. A method can be provided to ensure that the process time is significantly reduced. 0 The process according to the present invention can improve the homogeneity of the intermediate products in the mixing stages

Initial and pre-mix as well as the final product.

The present invention is now described with reference to the following examples:

Example: (1) Method:

Potassium bicarbonate bees are placed on sieves with AAA screen eyes Yoo 100 microliters

μl. Purified water is weighed and sodium picosulphate is dissolved in the water to form a sodium picosulphate solution for the pre-mixing stage. Sodium picosulphate solution is formed potassium rice 18006 in the form of granules using an offset coating method Jia (these coatings are well known in this field). Sodium picosulphate granules are filled into a coating medium; A certain amount of © sodium picosulphate solution is sprayed onto the surface of the particles during the operation of the coating medium. The filled particles are then dried with warm air. after the coating process; Pre-mixed dry granules of sodium picosulphate and potassium bicarbonate are obtained - Figure (7) shows SEM images, EDAX results and EDAX results for a pre-mixed granule in this method.

Vv. Premix granules using pS citric acids magnesium oxide mixing media are mixed; and add magnesium oxide; And 3D citric acid is added. A mixing media is filled with and SEM results (photo 1 JE light). saccharin sodium with the premix and a known quantity of a premix to form a flavoring blend.The flavoring mixture is then combined with the remainder of the premix and mixed with it.The powder of the final mixture is bagged and packed into carton boxes, using methods known in the art.It is noted that those with Experience in this field easily realize that the quantities of chemical agents and others, YY eg

Yo —— and to be used (eg in large-scale production operations) depending on the quantity of product desired. Example (7): Formulas: The following formulas have been prepared by the method described above); Each foil sachet© contains the following contents.

— Y 3 _ (Y) eg ("b) l i) ot zV) chemical eg (") . Example: Jalal) (a bag of gm).

Potassium 0 and 00 ° o < P and O O g 8 g 8 g Tho ¢ magnesium oxide : or a3 EDAX : or SEM analysis results Example (?): Photographs : Laboratory electron microscope on EDAX 5 SEM pictures were taken

Instrumentation Analysis and Research Centre, Sun Yat-sen University, China.

Claims (1)

No - Claims 1-1 A process for preparing a pharmaceutical composition comprising a homogeneous or substantially homogeneous mixture of potassium bicarbonate “magnesium oxide ¢ citric acid Y and sodium picosulphate” in the form of 1 optionally fruit flavor and flavor (Jl Comprising the step of mie spraying sodium picosulphate ¢ solution on potassium bicarbonate ¢ and drying sodium picosulphate potassium bicarbonate 5 - 1"- process to prepare a composition comprising sodium picosulphate 5 potassium bicarbonate Jain Y on the step of applying (mie spraying) sodium picosulphate solution on potassium bicarbonate 1; and drying sodium picosulphate and potassium bicarbonate. <- Process according to claim (1) or Cus “(Y) of potassium bicarbonate having a particle size (diameter) range Y between about 001 µm and about 900 µm. 1 ;- process according to claim (1); (7) Or (oY) where the initial heating of potassium bicarbonate Y is done before it is placed (by spraying (Mia spraying) on a solution of sodium picosulphate on potassium bicarbonate ~~ Y . 1 #- a process according to any of protection (ASL) where sodium picosulphate and potassium bicarbonate 7 are dried at a temperature between Vo and 0100°C. 1 +- Process according to any of the EBL claims where drying is during de spraying ¥ and/or immediately or substantially immediately after de spraying ¥. YYYye¢ 1 7 “- A process according to any of the elements of protection AB where there are two or more times to place a solution of sodium picosulphate Y » and potassium bicarbonate 5 sodium picosulphate is dried during or immediately or substantially immediately after each application. Ade—A 1 according to any of the claims dal) wherein the product or composition formed by applying 7 (Mie spraying) a solution of sodium picosulphate on Potassium bicarbonate 1 and drying in the form of granules or particles 1 4- A process according to claim (4), where the granules or particles have an ans particle size (diameter) where more than ZA of particles having a particle size (diameter) between about 001" µm and about 0000 µm. -1 0 process under claim (A) or 0 6 where the granules have granules or particles "a particle size (had) distribution where less than 75 of the particles have an intracellular size (diameter) T greater than about 00 µm; and/or where less than 705 of the particles have ; particle size (diameter) less than about 100 µm. 1-11 process in accordance with any of the preceding claims wherein sodium picosulphate is in Y form an aqueous solution. 1-1 composition comprising sodium picosulphate 5 potassium bicarbonate prepared by a process in accordance with any of the claims from (1) to (11). Gu-1” 1 formulation including granules containing sodium picosulphate and potassium ) bicarbonate ¥ ; The granules include a layer of sodium picosulphate encapsulating a core of potassium bicarbonate ¥. -VE 1 composition according to claim (VF) wherein the granules have a particle size (diameter) distribution of 7 where more than TAS particles have a particle size (diameter) between about 100 µm F and about 500 µm. -1#1 Composition of claim (VF) or (61); where the granules have a particle size (Diameter) distribution where less than 75 of the particles have a particle size (Diameter) greater than about 1 0 micrometer and/or where less than 75% of the particles have a lower particle size (diameter). ; .of about 100 micrometers. -11-1 A process for preparing a pharmaceutical composition comprising a homogeneous or substantially homogeneous mixture of sodium picosulphate 5 potassium bicarbonate « magnesium oxide ¢ citric acid Y « » and in the form of saccharin sodium (ola) and/or orange flavouring; Comprising: ¢ (0) dry mixing of 8610 magnesium oxide 5 citric ¢ ° (b) application (eg by spraying) of a solution of sodium picosulphate on potassium bicarbonate 1 » and drying of potassium bicarbonate 5 sodium picosulphate mentioned; and V (c) mixing at least part of the product of step (1) with at least part of the product of step (b); A and optionally saccharin sodium and/or orange flavoring. YYY eg Initiate for -1#1 an operation according to claim (V1) in which step (a) contains an operation according to any of the ¥ claims (1 A) through 9 ¥—VA 1 operation according to the claim Claim (07) or (VY) in which step (b) contains a process according to “any of the claims from (©) to (11)-1#1. A process for preparing a pharmaceutical composition according to any of Claims (01) to (VV) ¥ comprise a further step (d) of mixing the product from step (c) with an additional amount of 1 dry-mixed mixture of magnesium oxide citric acid ¢ and/or product and then preparing By applying (spraying: for example) a solution of sodium picosulphate on sodium “assis potassium bicarbonate” potassium bicarbonate 5 picosulphate 5 - 0 - 1 process according to claim (51); where the amount of Others of a mixture of citric acid magnesium oxide Y containing some or all of the product from step 0) and/or prepared by a process “| in accordance with any of the claims from (OA) to (YT)- “71 1 process according to claim ©(01) (V9) wherein a further amount of the product formed “| by applying sodium picosulphate sla (Sia spraying) on potassium bicarbonate ¥ and drying contains some or all of the product from step (b) and/or prepared by a process pursuant to any 8 of claims (©) through (11). Ty - - VY 1 = Pharmaceutical preparation or composition comprising granules or a homogeneous or substantially homogeneous mixture of ¥ potassium bicarbonate « magnesium oxide 1 citric acid, sodium a picosulphate and optionally saccharin sodium and/or orange flavouring. 1 ??- a pharmaceutical composition according to claim (YY) in which the granule(s) have a particle size (diameter) range between about 001 and about 00 micrometers. 1;”- a pharmaceutical composition according to claim (YY) or (VY) in which the granule(s) have regular 7 sodium picosulphate content with an average value between about 0.4 and 28 » by weight. 7 1 ©?- A pharmaceutical composition obtained or that can be obtained by layering any of the “protection from (YY) (OT) 1 elements 1- A pharmaceutical composition containing granules of magnesium oxide 5 citric acid » and a second composition according to claim (VY) comprising granules potassium bicarbonate, sodium picosulphate “YF” and optionally saccharin sodium and/or orange flavouring. 77); wherein the resulting granule(s) have a particle size (diameter) Y range between about 001 and about 4000 µm. YA 1 pharmaceutical composition according to claim (771) or (YY) where is The granule(s) have a uniform Y content of sodium picosulphate with an average value between about 7020884 vrs vy — - * by weight. ) 4385-74 under any of the claims (YY) through (YA) for use as a laxative. YYye