Solid pharmaceutical preparation for peritoneal dialysis and process for producing the same

Abstract

The present invention relates to a novel solid pharmaceutical preparation for peritoneal dialysis comprising nucleating particles of sodium chloride coated with plurality of layers, wherein the plurality of layers comprises, a first layer (A) of sodium bicarbonate, second layer (B) comprising sodium chloride and dextrose, third layer (C) comprising the electrolytes calcium chloride and magnesium chloride, and the fourth outmost layer (D) comprising sodium lactate. The present invention also relates to a process for producing the novel solid pharmaceutical preparation.

Description

SOLID PHARMACEUTICAL PREPARATION FOR PERITONEAL DIALYSIS AND PROCESS FOR PRODUCING THE SAMEFIELD OF THE INVENTION

[0001] The present invention relates to a novel solid pharmaceutical preparation for dialysis, and more particularly, to a peritoneal dialysis solution precursor in multi-layered granulated or 3D printed solid form for preparing a dialysis solution for peritoneal dialysis and a process for producing the same.BACKGROUND

[0002] Due to various reasons, a person’s renal system can fail. Renal failure produces several physiological derangements. In such circumstances, it is no longer possible for a patient’s renal system to balance water and minerals or to excrete daily metabolic load. Toxic end products of metabolism, such as, urea, creatinine, uric acid and others, may accumulate in a patient’s blood and tissue.

[0003] Reduced kidney function and, above all, kidney failure is treated with dialysis. Dialysis removes waste, toxins and excess water from the body that normal functioning kidneys would otherwise remove. Dialysis treatment for replacement of kidney functions is critical to many people because the treatment is lifesaving.

[0004] One type of kidney failure therapy is peritoneal dialysis (“PD”), which infuses a dialysis solution, also called as dialysis fluid or dialysate or PD fluid, into a patient's peritoneal chamber via a catheter. The PD fluid comes into contact with the peritoneal membrane in the patient’s peritoneal chamber. Waste, toxins and excess water pass from the patient’s bloodstream, through the capillaries in the peritoneal membrane, and into the PD fluid due to diffusion and osmosis, i.e., an osmotic gradient occurs across the membrane. An osmotic agent in the PD fluid provides the osmotic gradient. Finally, the used PD fluid is drained from the peritoneal cavity of the patient, removing waste, toxins and excess water. This cycle is repeated multiple times in severe cases.

[0005] There are various types of peritoneal dialysis therapies, including continuous ambulatory peritoneal dialysis ("CAPD"). automated peritoneal dialysis (“APD”), tidal flow dialysis and continuous flow peritoneal dialysis (“CFPD”). CAPD is a manual dialysis treatment. Here, the patient manually connects an implanted catheter to a drain to allow used PD fluid to drain from the patient’s peritoneal cavity. The patient then switches fluid communication so that the patient catheter communicates with a bag of fresh PD fluid to infuse the fresh PD fluid through the catheter and into the patient. The patient disconnects the catheter from the fresh PD fluid bag and allows the PD fluid to dwell within the patient’s peritoneal cavity, wherein the transfer of waste, toxins and excess water takes place. After a dwell period, the patient repeats the manual dialysis procedure, in many instances, up to four times per day. Manual peritoneal dialysis requires a significant amount of time and effort from the patient, leaving ample room for improvement.

[0006] APD is similar to CAPD in that the dialysis treatment includes drain, fill and dwell cycles. APD machines, however, perform the cycles automatically, typically while the patient sleeps. APD machines free patients from having to manually perform the treatment cycles and from having to transport supplies during the day. APD machines connect fluidly to an implanted catheter, to a source or bag of fresh PD fluid and to a fluid drain. APD machines pump fresh PD fluid from a dialysis fluid source, through the catheter and into the patient’s peritoneal chamber. APD machines also allow for the PD fluid to dwell within the chamber and for the transfer of waste, toxins and excess water to take place. The source may include multiple liters of dialysis fluid or dialysate, including several solution bags.

[0007] Any of the above treatment modalities may operate with premade, e.g., bagged, solutions or dialysates which are typical for any type of PD (CAPD or APD).

[0008] Currently, dialysates for peritoneal dialysis are only available as solution. The manufacturing process involves dissolution of dialysates (osmotic agent, electrolytes, and buffers) in water which are filled into different volume of container / bags. In cases where a dialysis solution comprises sodium bicarbonate as buffer, two different solutions are prepared separately, a glucose solution (containing glucose and electrolytes Ca++, Mg++) and a bicarbonate solution (containing sodium bicarbonate, sodium lactate and electrolytes). Glucose and bicarbonate solutions are filled separately into two different chambers within the samebag, thereby preventing the interaction between bicarbonate and Ca++, Mg++ ions to eliminate the formation of precipitation.

[0009] Dialysates are supplied to the dialysis clinic or in the patient home in solution form (peritoneal dialysis solution) having different concentrations of an osmotic agent (1.5%, 2.5% and 4.25 % Glucose monohydrate) along with other electrolytes and also buffering agent (Lactate and / or Sodium Bicarbonate). The pH of glucose solutions and bicarbonate solutions is adjusted with pH adjusting agents (carbon dioxide, hydrochloric acid, sodium hydroxide). Such a requirement for an additional pH adjusting agent results in relatively higher operational cost.

[0010] Further, peritoneal dialysis solutions which are available in the market contain <5% of total solid content and -95% of water and are available mainly in bags having volumes of 1.5 litres, 2 litres, 2.5 litres, 5 litres, and 6 litres. As a result, patients have to carry and store significant amounts of solution bags and weight which causes inconvenience.[0001 1] Furthermore, the precise composition of the dialysate, specifically the amount of glucose to be used in a specific dialysis session may have to be determined by a doctor's prescription and as per therapy requirements. Pre-bagged dialysis solutions are available in only specific concentrations and volumes which creates a challenge in providing a patient customized medication approach as the solutions cannot be formulated based on patient needs, thereby limiting doctors from individualizing or personalizing the therapy only with the option available with ready solution bags.

[0012] Furthermore, since water contributes to about 95% of the weight of the solution bag, large storage spaces and warehouses are required for storing the bags / containers and higher operational and shipping cost of the product and consequently higher product / therapy cost is involved. Longer contact time between solution and bag / container may also pose leaching risks.

[0013] A need, therefore, exists for reducing the burden on those preparing and handling the dialysis solutions and for minimizing the risk of leaching, thereby improving patient safety, while also reducing the storage space and overall cost of the product and therapy.

[0014] For each of the above reasons, it is desirable to provide a solid pharmaceutical preparation for peritoneal dialysis which has improved stability, improved productivity at a lower cost, reduced storage and shipping cost and improved patient convenience and safety, and which can be used to prepare the final dialysis solution where and when it is needed.

[0015] Different types of solid pharmaceutical preparations for dialysis have been proposed in the art, such as those that are obtained by mixing the necessary components for a dialysis solution as granules or powders, or by coating necessary ingredients on a nucleating particle (Japanese Patent No. 2846883, Japanese Patent No. 2739898. and JP-A 10-259133). Nonetheless, these pharmaceutical preparations have a potential challenge that sodium bicarbonate, calcium salt, and magnesium salt directly contact each other, potentially leading to their reaction with crystallization water present in the calcium and magnesium salts, or the moisture in the air, to form sparingly soluble salts. Furthermore, an additional issue arises since sodium bicarbonate and acetic acid are in contact with each other and can react to generate carbon dioxide, thus hindenng the pH of the dialysis solution from being maintained at an appropriate range (Japanese Patent No. 2846883 and Japanese Patent No. 2739898).

[0016] A pharmaceutical formulation for dialysis having sodium bicarbonate in its innermost layer and sodium diacetate as an acid in its outermost layer (JP-A 10-259133) can create carbon dioxide upon breaking down of sodium bicarbonate in the inner layer due to the heat or water that is added in subsequent steps. Further, the heat and w ater generated by the decomposition of sodium bicarbonate may lead to the decomposition of glucose in the solid pharmaceutical preparation for dialysis. Furthermore, when the acetic acid from sodium diacetate is quickly released, it can react with sodium bicarbonate generated carbon dioxide, thereby altering the pH of the dialysis solution.

[0017] Preparing a solid pharmaceutical preparation for dialysis is therefore challenging in terms of selecting appropriate components and concentrations to produce stable solid granules of the pharmaceutical preparation.

[0018] In view' of these challenges, very few solid pharmaceutical preparations for dialysis containing all components required for dialysis in a single composition have been prepared,even less so successfully. In one pharmaceutical formulation, sodium bicarbonate is coated with an organic acid, calcium salt, or magnesium salt so that neither comes into touch with the other and no reaction occurs (JP-A 6-335527, JP-A 8-169836, JP-A 8-92071, and JP-A 11- 114054). Another granulated pharmaceutical preparation for dialysis has been made by combining sodium bicarbonate, calcium salt, magnesium salt, and solid organic acid while separately granulating the sodium bicarbonate. The resulting mixture contained all the elements required for dialysis (JP-A 6-335528 and JP-A 8-92070), however, it is likely that in these solid pharmaceutical preparations for dialysis, when pH adjusting agents, such as a solid organic acid and sodium acetate, come into contact with one another, the solid organic acid reacts with the sodium acetate to create free acetic acid, and that the acetic acid when vaporised reacts with the sodium bicarbonate to produce carbon dioxide.

[0019] A solid pharmaceutical preparation for dialysis has also been reported wherein ingredients are prepared by mixing calcium salt, magnesium salt, solid organic acid, sodium bicarbonate, and glucose coated respectively with sodium citrate (JP-A 10-87478). Another reported a solid pharmaceutical preparation for dialysis contained sodium bicarbonate, solid organic acid, calcium salt, and magnesium salt, each of which had been coated with potassium chloride or sodium chloride (JP-A 10-330270). However, it is difficult to attain uniformity7of the ingredients in the solid pharmaceutical preparations for dialysis that contains solid organic acid in a small amounts and / or mixtures of calcium salt and magnesium salt in powder form.

[0020] W02004067014A1 discloses a solid agent for dialysis which contains a composition of sodium chloride, potassium chloride, calcium chloride, magnesium chloride, and sodium acetate, a pH regulator, and glucose. Said composition is prepared from a mother particle / grain which contains sodium chloride, and a coating layer which contains glucose and magnesium chloride. The composition can be used together with a formulation of solid sodium bicarbonate. The layer(s) are coated onto each other by a spray-dry ing method, so the final solid agent is granular. However, in this preparation, the bicarbonate is directly added to the granules which mav result in a reaction of the bicarbonate with electrolytes.

[0021] US6923987B2 discloses a solid preparation for dialysis which is provided by separately granulating a composition comprising electrolytes except for sodium bicarbonate and a composition comprising a sugar component, and then mixing the compositions with anacid to produce the solid preparation. However, this prior art employs more than one preparation step for producing granules.

[0022] US6407070B1 discloses bicarbonate containing particles which are prepared and kept separate from other granules that comprise sodium chloride as base particle onto which a combination of electrolytes (calcium chloride, magnesium chloride and / or potassium chloride) is coated together with sodium acetate and glucose, followed by acetic acid. This strategy however needs an additional processing step and fails to disclose a unidirectional process flow or continuous manufacturing process which negatively impacts optimized usage of equipment, time, and cost.

[0023] US6489301B1 discloses a solid pharmaceutical preparation for haemodialysis with a plurality of layers comprising a first layer of sodium acetate on the nucleating particle of sodium chloride, second layer selected from calcium chloride, magnesium chloride potassium chloride and sodium chloride, third layer containing solid organic acid, a fourth layer containing glucose powder and fifth layer containing sodium bicarbonate powder. However, the solid preparation of this prior art is for preparing dialysate for haemodialysis and discloses compositions having glucose and citric acid layers adjacent to each other which may lead to formation of esters, thereby leading to a reduction of the amount of glucose and citric acid in the formulation. Further, while acetate-containing haemodialysis solutions have been used for many years, disadvantages of this routine have been reported, since acetate seems to contribute to the development of dialysis complications such a nausea, vomiting, headache, hypotension, and lassitude. Further, use of acetate-containing fluids is not suitable for peritoneal dialysis since the peritoneum would be exposed to lower pH for a long period of time.SUMMARY

[0024] The instant disclosure provides a novel solid pharmaceutical preparation in multilayered. granulated, or 3D printed solid form which acts as a ‘peritoneal dialysis solution precursor’ for preparing a dialysis solution for peritoneal dialysis, and a process for producing the same. Disclosed embodiments provide a multi-layered solid pharmaceutical preparation for peritoneal dialysis comprising all the constituents in a single granular composition, which has remarkable stability and uniformity of constituents present therein, avoids the use ofsodium acetate and organic acid such as citric acid, and is capable of preventing reactions between sodium bicarbonate and electrolytes.

[0025] As a result of extensive experimentation conducted by the present inventors for solving the problems described above and to provide a stable solid pharmaceutical preparation for peritoneal dialysis, disclosed herein is a solid pharmaceutical preparation in multi-layered granulated or 3D printed solid form which comprises a plurality of layers in the order of sodium bicarbonate coated on a nucleating particle of sodium chloride, glucose and sodium chloride, magnesium chloride and calcium chloride, and sodium lactate as the outermost layer.

[0026] Thus, in one embodiment, the present invention relates to a solid pharmaceutical composition for peritoneal dialysis comprising nucleating particles of sodium chloride which are coated with a plurality of layers, wherein the plurality of layers comprises, a first layer (A) of sodium bicarbonate, a second layer (B) comprising of sodium chloride and dextrose, a third layer (C) comprising of the electrolytes calcium chloride and magnesium chloride, and the fourth and outermost layer (D) compnsing sodium lactate.

[0027] In another embodiment, the present invention relates to a solid pharmaceutical composition wherein the nucleating particles of sodium chloride which are coated with layers (A-D) further comprise a layer (E). preferably in the form of granular powder.

[0028] In yet another embodiment, the present invention relates to a solid pharmaceutical composition wherein the multi-layered granules comprise sodium chloride, sodium bicarbonate, dextrose monohydrate, calcium chloride dihydrate, magnesium chloride hexahydrate and sodium L lactate.

[0029] In another embodiment, the present invention relates to a multi-layered solid pharmaceutical composition wherein the multi-layered granule comprises sodium chloride, dextrose monohydrate, calcium chloride dihydrate, magnesium chloride hexahydrate and sodium L lactate.

[0030] In yet another embodiment, the present invention relates to a solid pharmaceutical composition wherein addition of pH adjusting agent such as carbon dioxide, hydrochloric acid,sodium hydroxide etc. may not be required in the reconstituted solution, thereby reducing the operational cost.

[0031] In one embodiment, the present invention relates to a process for producing a solid pharmaceutical composition for peritoneal dialysis comprising coating the nucleating particles of sodium chloride with layers comprising a first layer (A) of sodium bicarbonate, a second layer (B) comprising of sodium chloride and dextrose, a third layer (C) comprising the electrolytes calcium chloride and magnesium chloride, and a fourth and outermost layer (D) comprising sodium lactate.

[0032] In another embodiment of the process, the present invention is directed to a process for producing a solid pharmaceutical composition for peritoneal dialysis, comprising the steps of:(a) Providing core granules of sodium chloride as nucleating particles,(b) Applying an aqueous solution of sodium bicarbonate to the surface of the nucleating particles, and drying the resulting particles to form a first layer (A),(c) Adding a dry mix of glucose monohydrate and applying a coating solution containing dextrose monohydrate and sodium chloride onto the surface of the particles obtained in step (b), and drying the resulting particles to form a second layer (B),(d) Applying an aqueous solution containing calcium chloride dihydrate and magnesium chloride hexahydrate onto the surface of the particles obtained in step (c) and drying the resulting particles to form a third layer (C), and(e) Applying an hydroalcohilic solution containing sodium lactate to the particles obtained in step (d) and drying the particles to form a fourth layer (D).

[0033] In yet another embodiment of the process, the process comprises step (f):(I Adding / mixing glucose monohydrate powder to the particles obtained in step (e), to obtain a solid pharmaceutical preparation for use in the generation of a dialysis fluid for peritoeal dialysis applications.

[0034] In one embodiment of the invention, the present invention relates to a peritoneal dialysis solution comprising a reconstituted solid pharmaceutical preparation of the invention.

[0035] In another embodiment of the invention, the present invention relates to a peritoneal dialysis solution prepared from the solid pharmaceutical preparation produced by the process of the invention.BRIEF DESCRIPTION OF THE DRAWINGSThe summarj; as well as the following detailed description, are further understood when read in conjunction with the appended drawings. For illustrating the invention, there are shown, in the drawings, exemplary embodiments of the invention. However, the invention is not limited to the specific disclosure of the drawings.

[0036] Figure 1 is a diagrammatic representation of multi-layered granular solid pharmaceutical preparation as prepared in Example 3.[00037J Figure 2 is an illustration showing the process for producing the solid pharmaceutical preparation of multi-layered granules according to the invention.

[0038] Figure 3 provides the observation of the product stability of the solid pharmaceutical preparation of multi-layered granules upon storage for 3 months at room temperature.DETAILED DESCRIPTION OF THE INVENTION

[0039] The disclosure may be more fully appreciated by reference to the following description, including the following glossary of terms and the concluding examples It is to be appreciated that certain features of the disclosed solid pharmaceutical preparation and related processes which are, for clarity7, described herein in the context of separate aspects, may also be provided in combination in a single aspect. Conversely, various features of the disclosed solid pharmaceutical preparation and related processes that are, for brevity, described in the context of a single aspect, may also be provided separately or in any subcombination.

[0040] Some of the quantitative expressions given herein are not qualified with the term "‘about”. It is to be understood that whether the term “about” is used explicitly or not, even’ quantify given herein is meant to refer to the actual given value, and it is also meant to refer to the approximation to such given value that would reasonably be inferred based on the ordinary skill in the art, including approximations due to the experimental and / or measurement conditions for such given value. The terms "about" or "approximately" as used herein, when referring to a numerical value or range, allow for a degree of variability in the value or range, for example, within 10% (i.e., ±10%), within 5% (i.e., ±5%), or within 2.5% (i.e., ± 2.5%) of a stated value or of a stated limit of a range.

[0041] Throughout the description and claims of this specification, the words “comprise” and “contain” and variations of the words, for example “comprising” and “comprises”, mean “including but not limited to”, and are not intended to (and do not) exclude other components.

[0042] The recitation of numerical ranges by endpoints includes all integer numbers and, where appropnate, fractions subsumed within that range (e.g. 1 to 5 can include 1, 2. 3. and 4 when referring to, for example, a number of elements, and can also include 1.5, 2, 2.75 and 3.80, when referring to, for example, measurements). The recitation of end points also includes the end point values themselves (e.g. from 1.0 to 5.0 includes both 1.0 and 5.0). Any numerical range recited herein is intended to include all sub-ranges subsumed therein.

[0043] All references cited in the present specification are hereby incorporated by reference in their entirety. In particular, the teachings of all references herein specifically referred to are incorporated by reference.

[0044] Reference throughout this specification to "one embodiment" or "an embodiment" means that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment of the present invention. Thus, appearances of the phrases "in one embodiment" or "in an embodiment" in various places throughout this specification are not necessarily all referring to the same embodiment, but may do so. Furthermore, the particular features, structures or characteristics may be combined in any suitable manner, as would be apparent to a person skilled in the art from this disclosure, in one or more embodiments.

[0045] Furthermore, while some embodiments described herein include some but not other features included in other embodiments, combinations of features of different embodiments are meant to be within the scope of the invention, and form different embodiments, as would be understood by those in the art.

[0046] The terms "a,” "‘an,” "‘the”, and similar references used in the context of describing the disclosure (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., "such as") provided herein is intended merely to better illuminate the disclosure and does not pose a limitation on the scope otherwise claimed. No language in the present specification should be construed as indicating any non-claimed element essential to the practice of embodiments disclosed herein.

[0047] The term “room temperature” (RT) refers to a temperature of from about 15°C to about 30°C, in particular from about 20°C to about 30°C. Preferably, room temperature is a temperature of about 25 °C.

[0048] The terms “solid pharmaceutical preparation”, “solid pharmaceutical composition”, “peritoneal dialysis solution precursor”, “multi-layered granulated form” or “3D printed solid form” are herein used interchangeably.

[0049] The term “dialysis” refers to the medical procedure of removing waste products and extra fluid from the body of the subject when the kidneys do not function properly.

[0050] The term “peritoneal dialysis” refers to a procedure that uses the lining of the peritoneum as a filter wherein a special solution is placed in the abdomen and allowed to dwell there for a period of time, thereby absorbing waste products and extra fluid from the blood, followed by draining the solution from the abdomen.

[0051] The terms “dialysate” and “dialysis solution” which can be interchangeably be used, refer to a solution of water, electrolytes, and other substances which are used in dialysis procedures to remove waste products and excess fluids from the body of the subject.

[0052] The term “multi-layered granules” refers to solid dosage forms that consists of two or more layers made of different constituents.

[0053] The term “3D printed solid dosage form” (3DP SF) refers to a pharmaceutical dosage form that is created using 3D printing technology'.

[0054] The term “nucleating particles” refers to base granules used in multi-layered granules onto which at least one further layer is being applied.

[0055] The term “reconstituted solid pharmaceutical preparation” refers to a solid pharmaceutical preparation that is reconstituted to solution form before administration.

[0056] The term “fluidized-bed granulation” refers to a method of producing granules from a powder by suspending the powder in a fluidized bed and spraying a binder liquid onto the particles to form granules. As used herein, the term “applying”, “apply” to the surface of a particle preferably means “spraying” or “spray”.

[0057] The term “fluidized bed processor” refers to an instrument that uses the principle of fluidization to process solid materials, where solid material is converted from a static solidlike state to a dynamic fluid-like state by the introduction of a gas or liquid at a high enough velocity.Solid pharmaceutical preparations

[0058] The solid pharmaceutical preparation of the present invention is a multi-layered granulated or 3D printed solid form which acts as a ‘peritoneal dialysis solution precursor’ for preparing a dialysis solution for peritoneal dialysis. Disclosed embodiments provide a multilayered solid pharmaceutical preparation for peritoneal dialysis comprising all the constituents in a single granular composition, which has remarkable stability and uniformity of constituentspresent therein, avoids the use of sodium acetate and organic acids such as, for example, citric acid, and is capable of preventing a reaction between sodium bicarbonate and electrolytes.

[0059] The solid pharmaceutical preparation of the present invention comprises a plurality of layers in the order of a nucleating particle of sodium chloride which forms the core of a given particle and which is coated, in that order, with sodium bicarbonate, glucose and sodium chloride, magnesium chloride and calcium chloride, and sodium lactate as the outermost layer.

[0060] In one aspect of the invention, the solid pharmaceutical preparation for dialysis according to the present invention preferably comprises, where applicable, glucose monohydrate (glucose anhydrous), sodium chloride, calcium chloride dihydrate, magnesium chloride hexahydrate, sodium lactate.

[0061] In another aspect of the invention, the solid pharmaceutical preparation for dialysis according to the present invention comprises, where applicable, glucose monohydrate (glucose anhydrous), sodium chloride, calcium chloride dihydrate, magnesium chloride hexahydrate, sodium lactate and sodium bicarbonate.

[0062] In the present invention, sodium lactate is used in solution form and sprayed on the granules and dried to form a solid layer of sodium lactate.

[0063] In an embodiment of the present invention, the solid pharmaceutical preparation for dialysis is preferably a multi-layered particle consisting of a nucleating particle and 4 layers consecutive layers consisting of a first, second, third, and fourth layer on said nucleating particle. A group of preferable compounds forming each layer in said particles is as follows (Refer Fig 1):Nucleating particles : Sodium ChlorideFirst layer : Sodium BicarbonateSecond : Glucose and Sodium ChlorideThird layer : Calcium Chloride and Magnesium ChlorideFourth layer : Sodium Lactate

[0064] The solid pharmaceutical preparation for dialysis according to the present invention is a coated particle comprising sodium chloride as nucleating agent over which other ingredients are coated on top of one another to form different layers. The respective ingredients are dissolved to form aqueous or hydroalcoholic solutions which are then preferably sprayed on the previous particle or layer in a consecutive manner, followed in each case by drying to form the multi-layered granules. This is followed by additionally adding glucose to the multi-layered granules in the form of powder.

[0065] The coated granules of the invention are multi-layered granules wherein the layers of the said multi-layered granules as described above are separated to prevent sodium bicarbonate and electrolytes (Calcium Chloride and Magnesium Chloride) from coming into contact with each other.

[0066] In one aspect of the invention, the solid pharmaceutical composition consists of multilayered granules wherein the addition of pH adjusting agents such as carbon dioxide, hydrochloric acid, sodium hydroxide etc. is not required in the reconstituted solution, thereby reducing risks and operational costs.Process for producing solid pharmaceutical preparations

[0067] The solid pharmaceutical preparation for dialysis according to the present invention can be produced by fluidized-bed granulation using a fluidized bed processor, 3D Printing technology, or a combination thereof.

[0068] One embodiment of the process for producing the solid pharmaceutical preparation of the present invention is shown in Figure 2 and is further described here below:1) First, 40 to 60% total amount of sodium chloride with a particle diameter in the range from 0.5-2 mm as nucleating particles are introduced into a granulation drying unit for fluidizing, e.g., by an upward air flow which creates a circular product movement. The particles are then sprayed with an aqueous solution of sodium bicarbonate in the range of 5-25% and dried to form a first layer of sodium bicarbonate on the nucleating particles, wherein at least a part of the surface, preferably 75% to 95% or 80% to 98% of the surface, or the completesurface (100% of the surface) of the sodium chloride nucleating particles is coated with said sodium bicarbonate. The spraying method involves spraying the particles with the aqueous sodium bicarbonate solution at an optimized spray rate for a specified time (minutes), depending on the batch size. The process parameters which can advantageously be used are shown in below Table I. The drying is preferably continued at around 50° C for 10 minutes at the end of spraying.Table I: Process parameters for applying the first layer2) The first layered product obtained in step (1) is submitted to the application of a second layer, wherein the particles of step (1) are introduced into the processor together with glucose (25% -35% of the batch quantity) having a particle diameter less than 0.5 mm as a dry mixture, followed by spraying with an aqueous solution (45 - 55% solution) containing glucose ( 15% - 25% of the batch quantity ) and sodium chloride (~ 50% of the batch quantity' ) at an optimized spray rate and then dried at about 60°C for 10 minutes whereby glucose powder in dry mixture and solution is allowed to adhere to the surface of the product to form a second layer thereon. The process parameters which can advantageously be used for applying the second layer are shown in below Table II.Table II: Process parameters for applying the second layer3) An aqueous solution (10-30%) of magnesium chloride and calcium chloride is sprayed onto the layered granules obtained in step (2) for a certain time (~50 minutes) as per the following process parameters (see Table III). The granules are then dried at about 60° C for 10 minutes to form a third layer. The water content in the granulated product after drying is preferably less than 1.0%.Table III: Process parameters for apply ing the third layer4) The granules from step (3) are then coated with a (15-35%) hydroalcoholic solution of sodium lactate at an optimized spray rate and then dried at 40°C to 50°C, thereby allowing the sodium lactate to adhere to the surface of the product to form a fourth layer. The process parameters are shown in below Table IV. The granules are dried at 40°C for 5 minutes. Isopropyl alcohol is used as carrier to improve sodium lactate layering at a lower temperature which allowed spraying and adhesion of sodium lactate on step (3) granules. The water content in the product after drying is preferably less than 1.0%. After the fourth layer is formed, the particles are dried to remove the isopropyl alcohol content from the formulation.Table IV: Process parameters for applying the fourth layer5) Multi-layered granules produced in step (4) are further mixed with the remaining (40% to 50%) of dry' powder glucose from the batch quantity7, to obtain a solid pharmaceutical preparation for dialysis as the final multi-layered granulated product.EMBODIMENTS OF THE INVENTION

[0069] Preferred features, statements, and embodiments of the solid pharmaceutical preparation of the present invention and the process for preparing same are set forth herein below. Each statement and embodiment of the invention so defined may be combined with any other statement and / or embodiment unless clearly indicated to the contrary.1. A solid pharmaceutical preparation for preparing peritoneal dialysis solutions, wherein the pharmaceutical preparation comprises nucleating particles of sodium chloride which are coated with a plurality7of layers, and wherein the plurality of layers comprises a first layer (A) of sodium bicarbonate, a second layer (B) comprising of sodium chloride and dextrose (glucose), a third layer (C) comprising of calcium chloride and magnesium chloride, and a fourth outermost layer (D) comprising sodium lactate.2. The solid pharmaceutical preparation of statement 1, wherein the nucleating particles of sodium chloride coated with layers (A-D) are further coated with glucose monohy drate powder.3. The solid pharmaceutical preparation of statement 1, wherein the multi-layered granules are comprising sodium chloride, sodium bicarbonate, glucose monohydrate, calcium chloride dihydrate, magnesium chloride hexahydrate and sodium L lactate.4. A solid pharmaceutical preparation wherein the multi-layered granules are comprising sodium chloride, glucose monohydrate, calcium chloride dihydrate, magnesium chloride hexahydrate and sodium L lactate.The solid pharmaceutical preparation of statement 1 or 2 wherein the layers are separated from each other so as to prevent moisture penetration to the core granule. The solid pharmaceutical preparation of statement 1 to 5, wherein the total concentration of Na+in the granule is equivalent to 125-150 mMol / L in the reconstituted solution. The solid pharmaceutical preparation of statement 6, wherein the total concentration of Na+in the granule is equivalent to 125-132 mMol / L in the reconstituted solution.. The solid pharmaceutical preparation of statement 1 to 5, wherein the total concentration of glucose monohydrate in the granule is equivalent to the range of from 25-250 mMol / L in the reconstituted solution. The solid pharmaceutical preparation of statement 8, wherein total concentration of glucose monohydrate in the granule is equivalent to the preferred range of from 75-214 mMol / L in the reconstituted solution. The solid pharmaceutical preparation of statement 1, wherein the reconstituted solution of the multi-layered granule comprises 5.38 g / L sodium chloride, 2.1 g / L sodium bicarbonate. 0.184 g / L calcium chloride, 0.051 g / L magnesium chloride. 1.68 g / L sodium lactate and 15 g / L glucose monohydrate. The solid pharmaceutical preparation of statement 1, wherein the the reconstituted solution of multi-layered granule comprises 5.38 g / L sodium chloride, 0.21 g / L sodium bicarbonate, 0.184 g / L calcium chloride, 0.051 g / L magnesium chloride, 3.36 g / L sodium lactate and 15 g / L glucose monohydrate. The solid pharmaceutical preparation of statement 1, wherein calcium chloride dihydrate and magnesium chloride hexahydrate are present in the ratio of 0.5 :4.5 to 1 :4. A process for producing a solid pharmaceutical preparation for peritoneal dialysis comprising the steps of:(a) Providing core granules of sodium chloride as nucleating particles,(b) Spraying an aqueous solution of sodium bicarbonate onto the surface of the nucleating particles, and drying them to form a first layer (A),(c) Consecutively adding a glucose monohydrate dry mix and spraying a coating solution comprising glucose monohydrate and sodium chloride onto the particles obtained in step (b). and drying the particles to form a second layer (B),(d) Spraying an aqueous solution comprising calcium chloride dihydrate and magnesium chloride hexahydrate onto the particles obtained in step (c), and drying the particles to form a third layer (C), and(e) Spraying an hydroalcoholic solution comprising sodium lactate onto the particles obtained in step (d). and drying the particles to form a fourth layer (D). The process for producing the solid pharmaceutical preparation of statement 13, wherein the said process further comprises step (f), wherein(1) glucose monohydrate powder is mixed with the particles obtained in step (e), to obtain a solid pharmceutical preparation for dialysis, i.e.. the muhlayered granulated product. The process for producing the solid pharmaceutical preparation of statement 13 and / or statement 14, wherein the multi-layered granular formulation is prepared in a single stage multilayer fluidized bed coating. The process for producing the solid pharmaceutical preparation of statement 13-15, wherein the solvent for the coating solution is selected from the group comprising or consisting of water, methanol, ethanol, isopropyl alcohol, hydrogen peroxide, xylene, acetone, ethyl acetate, ethyl benzene, ethyl ether, methyl isobutyl ketone, n -butyl alcohol, and cyclohexanone. The process for producing the solid pharmaceutical preparation of statement 13-15 wherein the solid pharmaceutical preparation is produced by fluidized bed granulation using a fluidized bed processor.The process for producing the solid pharmaceutical preparation of statement 17, wherein the spray gun nozzle size is in the range of 0.5-1 mm. The process for producing the solid pharmaceutical preparation of statement 17, wherein the spray rate is in the range of 1- 30 RPM. The process for producing the solid pharmaceutical preparation of statement 13-17, wherein the granules are prepared at a temperature of 20-28 °C and humidity of 40- 60%. The process for producing the solid pharmaceutical preparation of statement 13-17, wherein the first layer (A) is produced by fluidized-bed granulation using a fluidized bed processor with an inlet temperature of 50- 85 °C, product temperature of - 30 - 45 °C, atomization pressure of 1.5 - 3.5 bar, blower speed of 45 -85 % and spray rate of 15-30 rpm. The process for producing the solid pharmaceutical preparation of statement 13-17, wherein the second layer (B) is produced by fluidized-bed granulation using a fluidized bed processor with an inlet temperature of 45 - 65 °C, product temperature of - 35 - 55 °C, atomization pressure of 1.5 - 2.5 bar, blower speed of 50-70% and spray rate of 2- 6 rpm. The process for producing the solid pharmaceutical preparation of statement 13-17, wherein the third layer (C) is produced by fluidized-bed granulation using a fluidized bed processor with inlet temperature of 45 - 65 °C, product temperature of - 40 - 55 °C, atomization pressure of 2.0 bar, blower speed of 50-60% and spray rate of 2-5 rpm. The process for producing the solid pharmaceutical preparation of statement 13-17, wherein the fourth layer (D) is produced by fluidized-bed granulation using a fluidized bed processor with inlet temperature of 40 - 50 °C, product temperature of - 35 - 45 °C, atomization pressure of 1.5 bar, blower speed of 50-60% and spray rate of 3-8 rpm.25. The process for producing the solid pharmaceutical preparation of statement 13-24, wherein in each layer the water content after drying is preferably less than 1.0%.26. A peritoneal dialysis dialysate comprising a reconstituted form of the solid pharmaceutical preparation of statement 1.27. A peritoneal dialysis solution prepared from the solid pharmaceutical preparation produced by the process of statement 13 or 14.All possible combinations of the above-identified embodiments are considered to be embraced within the scope of this invention.EXAMPLES

[0070] Reference is now made to the following examples, which illustrate the various embodiments of the present invention in a non-limiting manner.COMPARATIVE EXAMPLE 1ASSESSING THE FEASIBILITY OF APPLYING SODIUM LACTATE AS FIRST LAYER

[0071] In the following comparative example, the feasibility of applying sodium lactate as a first layer over the nucleating particles of sodium chloride was assessed by following the process steps as indicated in Table V.Table V

[0072] The process was started by loading 400.00 g of core Sodium chloride granules into a fluid bed coater bowl of fluidized bed processer. Before initiation of the coating process, preliminary trials were performed to check if fine particles of sodium chloride granules would be generated after loading. These granules were fluidized for 15 minutes at 60°C inlet temperature and 50% - 80% blower speed. After 15 minutes of run, only a negligible generation of fine particles was observed. Simultaneously, the Wurster column height was adjusted and various types of bottom plates like A, B & C were evaluated, and type C plate showed good flow pattern hence selected for further coating process.

[0073] To check the spray pattern, the solution was sprayed using a 1.00 mm spray gun nozzle adjusted with 0.6 bar atomization air and with a spray pump RPM set at 1 . With these selected parameters, the spray pattern was observed in a Wurster column and was found to be acceptable. The spray pump tube was changed to a narrow diameter model (3.0 mm) to get the minimal spray rate.

[0074] After completion of preliminary settings performed for finalization of the gun nozzle size, Wurster height, fluidization pattern, bottom plate type and spray pump tube size actual trial-runs were initiated.Trial-run 1 - At a product bed temperature of about 55°C spraying was initiated with above mentioned process parameters. Within few seconds of spraying, lump formation was observed for sodium chloride granules with observations of significant sticking on Wurster walls and bottom bowl walls. Spraying was stopped immediately, and granules were dried for 30 minutes at high fluidization (80% blower speed). Dried granules were found to be agglomerated.Trial -run 2 -In this run, to avoid lump formation issues that probably arise due to spraying of droplets from a 1 mm size nozzle, the nozzle size was changed to 0.8 mm and the inlet temperature was increased to 70°C. At a bed temperature of about 60°C, spraying w as initiated (atomization increased to 0.8 bar). Again, within few' seconds, formation of agglomerates w as observed. Spraying was stopped immediately, and granules were dried for 30 minutes at high fluidization (80% blower speed).Trial -run 3 -To avoid sticking and formation of agglomerates, bed fluidization was increased to 80% and the inlet temperature was increased to 80°C, upon reaching the bed temperature of about 70°C spraying initiated (atomization increased to 1.0 bar), again sticking was observed within few seconds. Immediately spraying was stopped and the granules were dried for 30 minutes at high fluidization (100% blow er speed).Trial -run 4 - From the experience of the above runs and observations, this run was focused on input materials like sodium lactate binder concentration. The initially 60 %w / w sodium lactate was diluted to 30% with purified water and the spraying w as started at a bed temperature of about 70°C. Again, sticking was observed within few' seconds. Immediately, spraying w as stopped, and the granules were dried for about 30 minutes at high fluidization (100% blower speed).Trial -run 5 - In this run, to check the impact of sodium lactate on the above issues only purified water was taken (without sodium lactate) and the spraying on sodium chloride granules was started at a bed temperature of about 70°C. Again, sticking was observed withinfew seconds. Immediately, spraying was stopped, and the granules were dried for 30 minutes at high fluidization (100% blower speed). Dried granules were found to be agglomerates and were passed through #20 ASTM and again used for coating.Trial -run 6 - From the above runs it was confirmed that usage of water should be avoided to overcoming the sticking and agglomerates formation. So, this run was used to check the feasibility of using organic solvents like isopropyl alcohol. 20 g of 60% sodium lactate was diluted with 80 g of isopropyl alcohol under stirring (lower dilutions found to be immiscible). The inlet temperature was decreased to 40°C and the spraying was started at 1 RPM with a bed temperature of about 40°C. Sticking of sodium chloride granules was not observed and an increased spray pump RPM (up to 6) turned out to be feasible. Upon 30 mins of spraying, the granules were dried at 50°C inlet temperature. The granules were passed through #20 ASTM and minimal agglomerates were found.

[0075] Based on the above observations, it was concluded that, since sodium chloride granules are very hygroscopic in nature, they absorb the water / moisture and form agglomerates or lumps in presence of aqueous solvents during the coating process. Therefore, it was concluded that sticking and lump formation is observed with sodium lactate whenever it is used as a first layer over the nucleating particles of sodium chloride.COMPARATIVE EXAMPLE 2ASSESSING THE COMPATIBILITY OF MAGNESIUM CHLORIDE, CALCIUM CHLORIDE, AND DEXTROSE MONOHYDRATE, AND FEASIBILITY OF USING SAME TO FORM A FIRST LAYER

[0076] The goal of this study was to check the feasibility of coating calcium chloride dihydrate, magnesium chloride hexahydrate, and dextrose monohydrate solution on sodium chloride granules by applying a Wurster coating technology, following the process steps as indicated in Table VI.Table VITrial -run 1 - The sodium chloride salt was sieved. Granules having passed #20 ASTM and retained by #30 ASTM were used for further batch processing as base granules. 10.65 g of calcium chloride dihydrate, 2.94 g of magnesium chloride hexahydrate and 491.736 g (20% of total batch quantity) of dextrose monohydrate were dissolved in 504 g of purified water (heated up to 70°C) as a 50% solid concentration (1 :1 ratio of solids:water). Approximately 311.00 g of sodium chloride granules were loaded into a fluid bed bottom spray bowl and the spraying process was started after reaching the bed temperature above 50°C. Sticking was observed and no advantage was observed even after increasing the bed temperature in terms of improving the process feasibility.Trial -run 2 - To check the process feasibility, the remaining materials of Trial -run 1 w ere diluted to 12.5% (w / w) by adding 150 g of purified water under stirring. Coating was initiated on fresh sodium chloride granules. However, the same sticking tendency was observed at an operating bed temperature range of 39-57°C.Trial -run 3 - To determine if the sticking issue is connected to sodium chloride or to dextrose monohydrate, water was sprayed through the bottom spray gun on the surface of fresh sodium chloride granules (#30 passed) at a bed temperature of 50-55°C. Spraying continued for 40minutes and the spray pump speed was increased to 10 RPM. No sticking was observed. In conclusion, sticking or settling of the bed at bottom of the bowl was found to be due to the dextrose monohydrate. It was concluded that Magnesium and Calcium Chloride layering in combination with dextrose monohydrate is not feasible.COMPARATIVE EXAMPLE 3ASSESSING FEASIBILITY OF APPLYING DEXTROSE MONOHYDRATE AS A SECOND LAYER

[0077] The goal of this study was to evaluate the feasibility of applying sodium bicarbonate as a 1stlayer coating on sodium chloride granules, dextrose monohydrate as a 2ndlayer coating on top of the 1stlayer, sodium lactate 60%, calcium chloride dihydrate, and magnesium chloride hexahydrate as a 3rdlayer on top of the 2ndlayer by following the process steps as indicated in Table VII.Table VII

[0078] The Sodium Chloride salt was sieved, and those granules having passed sieve #30 ASTM and which were retained by sieve #40 ASTM were used for batch processing as base granules. 80.94 g of sodium bicarbonate was dissolved in 800 g of purified water and stirred for 1 hour until a clear solution was obtained. 207.34 g of sodium chloride granules were loaded into a fluid bed bottom spray bowl and the spraying process was started after reaching the required bed temperature. A yield of 275 g was observed versus a theoretical yield of 287.94g.Accordingly, the applied manufacturing process is feasible with regard to sodium bicarbonate coating.

[0079] 400 g of dextrose monohydrate dissolved in 400 g of purified water as 50% solids (w / w) was stirred for 15 min at 70°C and a clear solution was obtained with a slightly yellow color. This solution is used for applying the 2ndlayer to the granules. In a first step, 275 g of 1stlayer coated (sodium bicarbonate coated on sodium chloride) granules are mixed with 275 g of dry dextrose monohydrate, and purified water was added by spraying to mix granules and dextrose monohydrate at a bed temperature of 40-43°C and prepare them for the coating with a second layer. After that, the 2ndlayer was prepared by spraying the above dextrose solution on the obtained granules of the preceding step at a bed temperature of 35- 39°C.

[0080] By applying dextrose monohydrate to the 1stlayer coated sodium chloride granules to form dry mix base granules, an improvement in subsequent dextrose layering was observed, if after spraying in intervals of 5 minutes the granules were fluidized for 5 minutes before the next spraying step. It was concluded that concentrated dextrose monohydrate solution spraying is not desirable, but that the chosen process as described above is a feasible improvement.COMPARATIVE EXAMPLE 4BATCH-STEP MULTI-LAYERED GRANULAR FORMULATION PREPARATION

[0081] The goal of this study was to evaluate multi-layered granules prepared in a step-wise process with different parts.

[0082] The multi-layered granules were then prepared by an alternative batch step-wise process following the process steps as indicated in Table VIII.Table VIII

[0083] PART A: The Sodium chloride granules (sorted #30 / 40) were taken for batch processing as core I base granules. For processing 1stlayer, Sodium bicarbonate solution was dissolved in purified water under stirring and within 15 minutes a clear solution was observed. Sodium bicarbonate solution spraying was initiated. Fine particle generation was observed after completion of coating of the total batch of sodium bicarbonate on the sodium chloride granules.

[0084] 2ndlayer: The 2ndlayer was prepared with 1stlayer-coated granules and dextrose monohydrate were loaded into a bottom spray bowl to serve as the base granules for coating with a 2ndlayer of dextrose monohydrate. To mix the dextrose and sodium chloride materials, approx. 300 g of purified water was sprayed over the granules. The 2ndlayer coating solution was prepared with Dextrose monohydrate dissolved under stirring in purified water (pre-heated to about 60°C) and to this sodium chloride fine granules were added and dissolved under continuous stirring. This coating solution was sprayed onto the water-sprayed granules mix of the previous step.Such batch process looked feasible, however, after 35 minutes of coating sticking and settling of the bed was observed. So, the spray rate was decreased from 10 RPM to 4 RPM and the process was continued until completion.

[0085] 3rdlayer: The 3rdlayer coating solution was prepared with calcium chloride dihydrate and magnesium chloride hexahydrate dissolved in purified water under stirring and a clear solution was observed within 15 minutes. The 3rdlayer coating solution was sprayed onto the 2ndlayer-coated granules. After deposition of the 3rdlayer, granules seemed to be very hygroscopic.

[0086] PART-B: Sodium lactate (60% solution) coating on sodium chloride granulesCoating of sodium lactate aqueous solution on sodium chloride granules was found to be not feasible as per evaluated manufacturing trials due to agglomeration and lump formation.Feasibility trial with hydroalcoholic Sodium lactate solution. The 60% sodium lactate was diluted solution with isopropyl alcohol (sodium lactate: isopropyl alcohol = 20:80) and to coat on sieve #20 / 30 ASTM sodium chloride granules. PART-A granules were used for this test, and the manufacturing feasibility was evaluated with the following batch manufacturing process parameters:• Quantity of PART-A granules: 150.00 g (an equivalent proportion of the batch size)• Quantity of sodium chloride granules used as per PART-B: 11.18 g (an equivalent proportion of the batch size)• Quantity of sodium lactate 60% : 17.47 g (an equivalent proportion of the batch size)• Quantity of isopropyl alcohol: 69.87 g

[0087] Manufacturing process: 17.47 g of sodium lactate 60% solution was mixed with 69.87 g of isopropyl alcohol (IPA) under stirring. Both phases seemed to be immiscible. Therefore, spraying was continued by continuing stirring of the solution. 150 g of PART- A granules and 11. 18 g of sodium chloride granules were loaded into the bottom spray bowl and the sodium lactate / IPA mixture was used for spraying.Coating looked feasible, but at the end of the process sticking was observed, which may have been caused by a separation of sodium lactate and IPA during spraying or in spray pump tube.

[0088] PART: C74.86 g of dextrose monohydrate granules were manually mixed with above PART-B granules in a polybag. The LOD of the resulting granules was found to be 0.25% at 55°C auto mode in an IR moisture analyzer.

[0089] PART-B & PART-C:The intention was to evaluate the feasibility of coating a sodium lactate 60% solution / IPA solvent mixture on PART-A coated granules. It was further intended to evaluate the feasibility of using dextrose monohydrate and sodium chloride granules for application on PART-B base granules in a Wurster coating process.Part of Base granules:Quantity of PART-A granules used: 150.00 g. Quantity' of PART-C Dextrose monohydrate used: 74.86 g. Quantity of sodium chloride granules to be used as per PART-B: 11.18 gBinder spray mixture:Quantity of sodium lactate 60% to be used: 17.47 g. Quantity' of isopropyl alcohol to be used:69.87 g.

[0090] Manufacturing process:17.47 g of sodium lactate 60% solution was mixed with 69.87 g of isopropyl alcohol under stirring. Both phases seemed to be immiscible. Therefore, spraying was carried out under continued stirring of the solution. 150 g of PART-A granules and 11.18 g of sodium chloridegranules were loaded into a bottom spray bowl and a mixture of sodium lactate and IPA was used for spraying.

[0091] The batch or step-wise process resulted in sticking and settling of the bed after 15 minutes of spraying, which may have been due to the presence of dextrose and the separation of sodium lactate from the sodium lactate / IPA mixture during spraying or in the spray pump tube. The appearance of the final coated product was found to be unacceptable.EXAMPLE 1ASSESSING FEASIBILITY OF EMPLOYING SODIUM BICARBONATE AS FIRST COATING LAYER

[0092] The goal of this study was to check the process feasibility of using sodium bicarbonate as a 1stcoating layer and dextrose monohydrate as a 2ndcoating layer on sodium chloride granules by following the process steps as indicated in Table IX.Table IX

[0093] Sodium chloride was sieved, and sieve #30 ASTM passed, and sieve #40 ASTM retained granules were taken for batch processing as base granules. 80.94 g of sodium bicarbonate was dissolved in 800 g of purified water and stirred for 1 hour until a clear solution was observed. 207.34 g quantity of sodium chloride granules were loaded into fluid bed bottom spray bowl and started the spraying process after reaching the required bed temperature.

[0094] Sticking was observed only above a spray rate of 30 RPM. It could be concluded that this happened because of the low bed temperature only while the rest of the manufacturing process looked feasible with sodium bicarbonate layering. Process loss was also observed to be minimal.

[0095] 20% of the batch quantity of dextrose monohydrate (327.584 g) were dissolved in 6224.096 g of purified water under stirring. On top of the granules having a first layer (sodium bicarbonate coated on sodium chloride granules) dextrose binder was sprayed at a bed temperature of 39-41 °C. The bed settled down immediately and sticking was observed, which is why the process was discontinued. Sodium bicarbonate coating on sodium chloride granules was found to be feasible. Sodium bicarbonate was selected as a first coating layer over sodium chloride.EXAMPLE 2OPTIMIZING DEXTROSE MONOHYDRATE LAYERING

[0096] To confirm the process feasibility, layering of dextrose monohydrate binder on sodium chloride granules + dextrose monohydrate granules was executed.

[0097] 308 g of sodium chloride granules (#30 / 40) and 308 g of dextrose monohydrate granules (#30 passed) were used as base granules. Water was sprayed on the said granules at a bed temperature of 42-44°C and the spray RPM was increased to 30 RPM. No sticking and settling was observed in 30 minutes. 600 g of dextrose monohydrate was dissolved in 600 g of purified water (as 50% solids) by heating at 70°C and under stirring.

[0098] Sticking was observed at continuous spraying of dextrose monohydrate binder on the above base granules mix. After every 4 minutes of continuous spraying 4 minutes offluidization were required to avoid sticking of the base granules. To overcome this sticking issue and check the feasibility of continuous spraying, 200 g of dextrose monohydrate were dissolved together with 40 g of sodium chloride in in 220 g of purified water under stirring and heating water up to 70°C.The dextrose and sodium chloride solution were sprayed onto the above granules (sodium chloride + dextrose monohydrate).

[0099] No sticking was observed by spraying of dextrose and sodium chloride as binder at a low spray rate up to 6 RPM, and the process was qualified as being feasible. In conclusion, dextrose monohydrate was selected as a second layer.EXAMPLE 3SINGLE STEP MULTI-LAYERED GRANULAR FORMULATION PREPARATION

[0100] The multi-layered solid granular formulation of the present invention was prepared by the single step preparation process as indicated in Figure 3 and following the process steps as indicated in Table XI below.Table XI

[0101] The configuration of a multi-layered granular formulation was as follows:Nucleating particles: Sodium chlorideFirst layer: Sodium bicarbonateSecond layer: Glucose & sodium chlorideThird layer: Calcium chloride & magnesium chlorideFourth layer: Sodium lactate

[0102] Step 1 - First, 50 to 70% total amount of sodium chloride with a specified particle diameter as nucleating particles were introduced into a granulation drying unit for being fluidized. The particles were coated by spraying with an aqueous solution of sodium bicarbonate and then dried to form a first layer. At least a part of the surface of the sodium chloride as nucleating particles was coated with said sodium bicarbonate. The spraying method involved spraying at an optimized spray rate for a specified time period (minutes). The process parameters employed in the preparation of a multi-layered granular formulation were as follows (Table XII). The drying was preferably continued at about 50° C for 10 minutes after spraying.Table XIIStep 2 - The first layered product obtained in step (1) was submitted to the next coating step. An aqueous solution containing glucose and sodium chloride was sprayed on the first layered product in combination with glucose having a defined particle diameter in a dry mixture for a specified time period (minutes) at an optimized spray rate and then dried at about 60°C for 10 minutes whereby glucose powder in the dry mixture and the solution was allowed to adhere to the surface of the product to form a second layer thereon. Following (Table XIII) parameters were used during the second layering.Table XIIIStep 3 - An aqueous solution of magnesium chloride and calcium chloride was sprayed on the layered granules obtained in step (2) for a certain time period as per the process parameters shown in Table XIV. The granules were then dried at about 60° C for 10 minutes to form a third layer. The water content in the granulated product after drying was preferably less than 1.0%.Table XIVStep 4 - Granules from step (3) were coated with a hydroalcoholic solution of sodium lactate at an optimized spray rate and then dried at 40 to 50°C thereby allowing the sodium lactate to adhere to the surface of the product to form a fourth layer. The process parameters are tabulated in below Table XV. The granules were dried at 40°C for 5 minutes. Isopropyl alcohol was used as carrier to improve sodium lactate layering at a lower temperature which allowed spraying and adhesion of sodium lactate on step (3) granules. The water content in the product after drying was preferably less than 1.0%. After the fourth layer was formed, the particles were dried to remove the isopropyl alcohol content from the formulation.Table XVStep 5 - Multi-layered granules produced in step (4) were further mixed with 40 to 50% of glucose with specified particle diameter to obtain a solid pharmaceutical preparation for dialysis as the final multi-layered granulated product.EXAMPLE 4STABILITY STUDY OF MULTI-LAYERED GRANULAR PHARMACEUTICAL COMPOSITIONS FOR PERITONEAL DIALYSIS

[0106] Results regarding the stability of granular pharmaceutical compositions for peritoneal dialysis (as of example 3) comprising a base granule of sodium chloride coated with plurality of layers, wherein the plurality of layers comprises, a layer (A) comprising sodium bicarbonate, a layer (B) comprising dextrose applied as dry' mix and sodium chloride which is sprayed on, a layer (C) comprising calcium and magnesium chloride, and a layer (D) comprising sodium lactate are shown in Table XVI.Table XVIIIEXAMPLE 5SOLID PHARMACEUTICAL PRODUCT OPTIMIZATION TO ACHIEVE PHYSIOLOGICAL pH OF THE RECONSTITUTED SOLUTION

[0103] An optimized formulation for a granular pharmaceutical composition for peritoneal dialysis comprising a base granule of sodium chloride coated with plurality of layers was proposed, wherein the layers comprise a layer (A) comprising sodium bicarbonate, a layer (B) comprising dextrose coated as a dry' mix and sodium chloride which is sprayed on, a layer (C) comprising calcium and magnesium chloride, and a layer (D) comprising sodium lactate, and wherein the concentration of bicarbonate and lactate was optimized to achieve physiological pH upon reconstitution.Table XVI

[0104] The appearance of granular pharmaceutical composition for peritoneal dialysis comprising a base granule of sodium chloride coated with a plurality of layers, wherein the plurality of layers comprises a layer (A) comprising sodium bicarbonate, a layer (B) comprising dextrose applied as dry' mix and sodium chloride which is sprayed on, a layer (C) comprising calcium and magnesium chloride, and a layer (D) comprising sodium lactate, was found acceptable. The pH of the reconstituted solution would be ~7-8.

[0105] While preferred embodiments of the present invention have been shown and described herein, it will be apparent to those skilled in the art that such embodiments are provided by way of example only. The disclosed embodiments are only illustrative of the principles of the subject matter disclosed herein and are not limited to only those described herein. Certain embodiments describe the best mode known to the inventor for earn ing out the invention described herein, and numerous variations, changes, and substitutions may occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention and that embodiments within the scope of these claims and their equivalents be covered thereby.

Claims

WE CLAIM:

1. A solid pharmaceutical preparation for preparing peritoneal dialysis solutions, wherein the pharmaceutical preparation comprises nucleating particles of sodium chloride which are coated with a plurality of layers, and wherein the plurality of layers comprises a first layer (A) of sodium bicarbonate, a second layer (B) comprising of sodium chloride and dextrose (glucose), a third layer (C) comprising of calcium chloride and magnesium chloride, and a fourth outermost layer (D) comprising sodium lactate.

2. The solid pharmaceutical preparation as claimed in claim 1, wherein the nucleating particles of sodium chloride coated with layers (A-D) are further coated with glucose monohydrate powder.

3. The solid pharmaceutical preparation as claimed in claim 1, wherein the multilayered granules are comprising sodium chloride, sodium bicarbonate, glucose monohydrate, calcium chloride dihydrate, magnesium chloride hexahydrate and sodium L lactate.

4. A solid pharmaceutical preparation wherein the multi-layered granules are comprising sodium chloride, glucose monohydrate, calcium chloride dihydrate, magnesium chloride hexahydrate and sodium L lactate.

5. The solid pharmaceutical preparation as claimed in claim 1 or claim 4 wherein the layers are separated from each other so as to prevent moisture penetration to the core granule.

6. The solid pharmaceutical preparation as claimed in claims 1 to 4, wherein the total concentration of Na+in the granule is equivalent to 125-150 rnMol / L in the reconstituted solution.

7. The solid pharmaceutical preparation as claimed in claim 6, wherein the total concentration of Na+in the granule is equivalent to 125-132 mMol / L in the reconstituted solution.

8. The solid pharmaceutical preparation as claimed in claim 1 to 5, wherein the total concentration of glucose monohydrate in the granule is equivalent to the range of from 25-250 mMol / L in the reconstituted solution.

9. The solid pharmaceutical preparation as claimed in claim 8, wherein total concentration of glucose monohydrate in the granule is equivalent to the preferred range of from 75-214 mMol / L in the reconstituted solution.

10. The solid pharmaceutical preparation as claimed in claim 1, wherein the reconstituted solution of the multi-layered granule comprises 5.38 g / L sodium chloride, 2.1 g / L sodium bicarbonate, 0.184 g / L calcium chloride, 0.051 g / L magnesium chloride, 1.68 g / L sodium lactate and 15 g / L glucose monohydrate.

11. The solid pharmaceutical preparation as claimed in claim 1 , wherein the the reconstituted solution of multi-layered granule comprises 5.38 g / L sodium chloride, 0.21 g / L sodium bicarbonate, 0.184 g / L calcium chloride, 0.051 g / L magnesium chloride, 3.36 g / L sodium lactate and 15 g / L glucose monohydrate.

12. The solid pharmaceutical preparation as claimed in claim 1, wherein calcium chloride dihydrate and magnesium chloride hexahydrate are present in the ratio of 0.5:4.5 to 1:4.

13. A process for producing a solid pharmaceutical preparation for peritoneal dialysis comprising:(a) Providing core granules of sodium chloride as nucleating particles,(b) Spraying an aqueous solution of sodium bicarbonate onto the surface of the nucleating particles, and drying them to form a first layer (A),(c) Consecutively adding a glucose monohydrate dry mix and spraying a coating solution comprising glucose monohydrate and sodium chloride onto the particles obtained in step (b), and drying the particles to form a second layer (B),(d) Spraying an aqueous solution comprising calcium chloride dihydrate and magnesium chloride hexahydrate onto the particles obtained in step (c), and dry ing the particles to form a third layer (C), and(e) Spraying an hydroalcoholic solution comprising sodium lactate onto the particles obtained in step (d), and dry ing the particles to form a fourth layer (D).

14. The process for producing the solid pharmaceutical preparation as claimed in claim 13, wherein the said process comprises step (f):(1) glucose monohydrate powder is mixed with the particles obtained in step (e), to obtain a solid pharmceutical preparation for dialysis, i.e., the mulilayered granulated product.

15. The process for producing the solid pharmaceutical preparation as claimed in claim 13 or 14, wherein the multi-layered granular formulation is prepared in a single stage multilayer fluidized bed coating.

16. The process for producing the solid pharmaceutical preparation as claimed in claims 13-15, wherein the solvent for the coating solution is selected from the group comprising or consisting of water, methanol, ethanol, isopropyl alcohol, hydrogen peroxide, xylene, acetone, ethyl acetate, ethyl benzene, ethyl ether, methyl isobutyl ketone, n-butyl alcohol, and cyclohexanone.

17. The process for producing the solid pharmaceutical preparation as claimed in claims 13-15 wherein the solid pharmaceutical preparation is produced by fluidized bed granulation using a fluidized bed processor.

18. The process for producing the solid pharmaceutical preparation as claimed in claim 17, wherein the spray gun nozzle size is in the range of 0.5-1 mm.

19. The process for producing the solid pharmaceutical preparation as claimed in claim 17, wherein the spray rate is in the range of 1-30 RPM.

20. The process for producing the solid pharmaceutical preparation as claimed in claims 13-17, wherein the granules are prepared at a temperature of 20-28 °C and humidity of 40-60%.

21. The process for producing the solid pharmaceutical preparation as claimed in claims 13-17, wherein the first layer (A) is produced by fluidized-bed granulation using a fluidized bed processor with an inlet temperature of 50- 85 °C, product temperature of- 30 - 45 °C. atomization pressure of 1.5 - 3.5 bar, blower speed of 45 -85 % and spray rate of 15-30 rpm.

22. The process for producing the solid pharmaceutical preparation as claimed in claims 13-17, wherein the second layer (B) is produced by fluidized-bed granulation using a fluidized bed processor with an inlet temperature of 45 - 65 °C, product temperature of - 35 - 55 °C, atomization pressure of 1.5 - 2.5 bar, blower speed of 50-70% and spray rate of 2- 6 rpm.

23. The process for producing the solid pharmaceutical preparation as claimed in claims 13-17, wherein the third layer (C) is produced by fluidized-bed granulation using a fluidized bed processor with inlet temperature of 45 - 65 °C, product temperature of - 40 - 55 °C, atomization pressure of 2.0 bar, blower speed of 50- 60% and spray rate of 2-5 rpm.

24. The process for producing the solid pharmaceutical preparation as claimed in claims 13-17, wherein the fourth layer (D) is produced by fluidized-bed granulation using a fluidized bed processor with inlet temperature of 40 - 50 °C, product temperature of - 35 - 45 °C, atomization pressure of 1.5 bar, blower speed of 50- 60% and spray rate of 3-8 rpm.

25. The process for producing the solid pharmaceutical preparation as claimed in claims 13-24, wherein in each layer the water content after drying is preferably less than 1.0%.

26. A peritoneal dialysis dialysate comprising reconstituted form of the solid pharmaceutical preparation as claimed in claim 1.

27. A peritoneal dialysis solution prepared from the solid pharmaceutical preparation produced by the process as claimed in claims 13 or 14

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