Self-lubricating co-processed excipient system for solid dosage forms

Abstract

The present invention relates to co-processed excipient compositions for solid-dose pharmaceutical formulations. Furthermore, the invention relates to a process for producing the co-processed excipient compositions and solid-dose pharmaceutical formulations containing the co-processed excipient compositions.

Description

[0001] Self-lubricating co-processed excipient system for solid dosage forms

[0002] Technical Field

[0003] The present invention relates to co-processed excipient compositions for solid-dose pharmaceutical formulations. Furthermore, the invention relates to a process for producing the co-processed excipient compositions and solid-dose pharmaceutical formulations containing the co-processed excipient compositions.

[0004] Background

[0005] Pharmaceutical formulations, especially solid-dose pharmaceutical formulations, such as tablets, require the use of an excipient system to formulate the desired active pharmaceutical ingredient (API). In both, granulation and direct compression, the excipient system is usually not made from a single component but a mixture of different components tailored for the APIs specific need. Usually, different excipient combinations are chosen from a vast group of fillers, binders, lubricants, disintegrants, surfactants, glidants and other excipient groups.

[0006] Combining two or more excipients during a physical process, results in the generation of a co-processed excipient system (co-processed excipient). This coprocessed excipient is defined to possess superior characteristics compared to the physical mixture of the same components. Additionally, co-processed excipients do not tend to segregate and show less inhomogeneity compared to physical mixtures leading to little tablet weight variations after tableting (Tranova et al. 2022). A chemical change during this process in not wanted as this would lead to a novel entity. The physical process takes place at a sub-particle level where particles of different natures are incorporated on the surface or within the core of the combined excipient particle. This can be achieved through homogenization that is followed by a physical process such as spray drying, granulation or other pharmaceutical technologies (Rojas, Buckner, and Kumar 2012).

[0007] The goal of co-processing is to achieve a material superior to the classical physical mixture of the respective components. Furthermore, disadvantages of individual components are targeted with co-processing. In addition to the filler, adding a lubricant to formulations to be compressed, requires an individual process. Due to insufficient flowability, dosing and feeding of lubricants poses challenges. Usually, the lubricant is added into the outer phase or dosed as an external lubrication into the dyes of the tablet press. The addition and coprocessing of a lubricant onto the co-processed excipient is targeting these formulation challenges. With the filler making up most of the formulation, the lubricant remains on the outer phase and therefore keeps the functionality (Tian 2012).

[0008] Besides combining two components, the idea of developing an all-in-one coprocessed excipient or ready-to-use co-processed excipients is very attractive for fast and easy formulation. In orally disintegrating formulations, formulation design is very sophisticated with excipients influencing the performance of the final dosage form.

[0009] Additionally, rising manufacturing trends, such as continuous manufacturing will require co-processed excipients that are designed and tailored with new critical quality attributes where all-in-one co-processed excipients will play a great role (Moreton et al. 2019).

[0010] As co-processing is defined as a physical process, classical pharmaceutical technologies are mainly applied as the resulting material comprises the chemically unmodified versions of applied components. Major technologies used are wet granulation and spray drying since these processes usually yield a uniform product and have the possibility for easy scale-up. Furthermore, technologies such as melt granulation, hot-meld extrusion, co-crystallization, co-precipitation or co-milling can be applied (Rojas, Buckner, and Kumar 2012).

[0011] Available all-in-one co-processed excipients are inter alia Kollitab (BASF) and PROSOLV EASYtab (JRS Pharma). Both excipients comprise a filler, binder, disintegrant and a lubricant. In both cases, the lubricant is sodium stearyl fumarate, a water soluble component. The filler component of Kollitab is Lactose. Lactose is prone to Malliard reaction as it represents a reducing sugar and therefore incompatabilites with certain APIs need to be carefully evaluated. The filler used for the PROSOLV EASYtab is microcrystalline cellulose. This excipient shows excellent behavior in tableting but is prone to water uptake which can be harmful for watersensitive APIs.

[0012] A co-processed excipient comprising the water-insoluble lubricant magnesium stearate (MSA) is Nu-tab (Ingredient Technology, Inc.). Besides sucrose, invert sugar and starch, it contains small amounts of magnesium stearate. The coprocessed excipient is mentioned in 1985 and cannot be purchased any more (Staniforth 1985).

[0013] The majority of co-processed excipients do not contain lubricants, especially magnesium or calcium stearate, due to the insolubility with water and challenging processing of these components. Therefore, most manufacturers suggest the addition of a lubricant in an additional mixing step before tableting.

[0014] MST is usually added in one of the last steps as its lubrication ability is linked to the MST forming layers on the surface of particles. The lubrication ability is directly linked to these layers.

[0015] It is an object of the invention to provide a co-processed excipient composition containing a lubricant, wherein the lubricant is effectively incorporated into the coprocessed excipient composition to ensure a suitable lubrication during tableting and I or wherein the co-processing step technically feasible.

[0016] Furthermore, there is a need for co-processed excipient compositions leading to solid-dose pharmaceutical formulations with a fast and quantitativ API release, a sufficient dissolution of the API and / or a suitable hardness and friability both for high and low API doses. The mixture of co-processed excipient compositions and API should show a suitable flowablity and I or compressability which can be applied in various manufacturing technologies covering batch or continuous manufacturing. Additionally, the co-processed excipient composition should be chemically inert, e.g. not prone to Malliard reaction, and not prone to water uptake.

[0017] It has now unexpectedly been found that when a pharmaceutical compression aid is co-processed with a pharmaceutical lubricant, the resulting product is selflubricating and when incorporated into solid-dose pharmaceutical compositions provides excellent lubrication and avoids the problems associated with the use of magnesium stearate alone as lubricant. Summary of the Invention

[0018] Surprisingly it was found that a co-processed excipient composition for solid-dose pharmaceutical formulation, comprising a) from about 75 percent to 97 percent by weight of at least one filler, b) from about 1 percent to 10 percent by weight of at least one poloxamer, c) from about 0.5 percent to 5 percent by weight of at least one hydrophilic binder, d) from about 1 percent to 5 percent by weight of at least one superdisintegrant, and e) from about 1 percent to 5 percent by weight of at least one lubricant can be beneficially used for the formulation of a solid-dose pharmaceutical formulation.

[0019] A further embodiment of the invention is a process for preparing a co-processed excipient composition for solid-dose pharmaceutical formulation as described above comprising the steps of a) combining the filler, amphiphilic polymer, hydrophilic binder, superdisintegrant and lubricant and b) co-processing the mixture by a method selected from the list comprising wet and dry granulation, fluidized bed granulation, roller compaction, spray drying, spray granulation, direct compression, melt extrusion, miling, surface adsorption, surface modification, dry coating, controlled crystallization, crystallo-coaglomeration.

[0020] In another aspect, the invention provides a solid-dose pharmaceutical formulation comprising co-processed excipient composition as described above.

[0021] Detailed Description of the Invention

[0022] An embodiment of the invention is co-processed excipient composition for soliddose pharmaceutical formulation, comprising a) from about 75 percent to 97 percent by weight of at least one filler, b) from about 1 percent to 10 percent by weight of at least one poloxamer, c) from about 0.5 percent to 5 percent by weight of at least one hydrophilic binder, d) from about 1 percent to 5 percent by weight of at least one superdisintegrant, and e) from about 1 percent to 5 percent by weight of at least one lubricant. According to the invention, the term “co-processed excipient composition” means a composition of pharmaceutical excipients, such as the components according to the invention, but not including an API, which have been processed together to form a single composition, preferably to form a physically bound composite of the components. Suitable co-processing methods include, but are not limited to, wet and dry granulation, spray drying, direct compression, melt extrusion, milling, surface adsorption, surface modification, dry coating, controlled crystallization or crystallo-coagglomeration. Preferably, the composition is co-processed by wet granulation or spray-drying, more preferably by spray-drying.

[0023] According to the invention, the term “solid-dose pharmaceutical formulation” means a pharmaceutical formulation suitable comprising at least one API and a coprocessed excipient composition as defined above for oral administration by an individual or a patient to be treated. Solid-dose pharmaceutical formulation can be formulated as tablets, pills, dragees, capsules and the like, for oral ingestion by an individual or a patient to be treated. Such solid-dose pharmaceutical formulation forms can be prepared by any known method of formulation. The co-processed excipient composition of the invention may be present in the solid-dose pharmaceutical formulation in an amount as low as about 30 percent by weight of the solid-dose pharmaceutical formulation, typically from about 30 percent to about 99 percent or preferably from about 50 percent to about 99 percent by weight of the solid-dose pharmaceutical formulation. Preferably, the solid-dose pharmaceutical formulation is a tablet.

[0024] According to the invention, the term “filler” means a substance which is suitable for use in a solid-dose pharmaceutical formulation and which helps achieve the desired compression characteristics of a powder material used for pharmaceutical tabletting or encapsulation.

[0025] Suitable filler for use in the co-processed excipient composition of the invention include lactose, microcrystalline cellulose, modified starch, mannitol, dextrose, cellulose, magnesium carbonate, dibasic calcium phosphate dihydrate, calcium sulphite dihydrate and tricalcium phosphate. Preferably lactose, microcrystalline cellulose and mannitol are used, more preferably mannitol is used. The mannitol may be a crystalline D-Mannitol, preferably a P-polymorph, wherein the content of the P-polymorph is higher than the content of the a- or b-polymorph. In one embodiment, the mannitol has a defined particle distribution. The particle size distribution is defined by D10 and D90, preferably measured by Dynamic Image Analysis. D10 and D90 represent the particle diameter corresponding to 10% (for D10) and 90% (for D90) cumulative (from 0 to 100%) undersize particle size distribution. In a preferred embodiment, the mannitol has a D10 of 20 or higher and a D90 of 400 or lower. In a more preferred embodiment, the mannitol has a D10 of 40 or higher and a D90 of 350 or lower.

[0026] Selecting mannitol as filler, both the water-uptake as well as the Malliard reaction are circumvented as compared to compositions containing lactose or microcrystalline cellulose.

[0027] Poloxamers according to the invention are amphiphilic polymers, with two hydrophilic blocks and a hydrophobic block in the middle. A poloxamer is a polyethylene glycol (PEG) / polypropylene glycol (PPG) tri-block copolymer whereby one PPG block is flanked on both sides with a PEG block. The polyethylene glycol (PEG) part is often also called polyethylene oxide (PEG) part. The polypropylene glycol (PPG) part is often also called the polypropylene oxide (PPO) part.

[0028] Poloxamer grades are commonly named with the letter P (for poloxamer) followed by three digits that is officially used by USP and EP. It describes the composition of the polymer as follows: the first two digits multiplied by 100 represents the molecular weight of the PO block and the last digit multiplied by 10 provides the percentage of EO in %.

[0029] Poloxamer P188 in average is composed of 80% EO, while the remaining 20% PO make up for 1800 g / mol. Poloxamer P407 is a poloxamer with an average polyoxypropylene molecular mass of 4000 g / mol and a 70% polyoxyethylene content.

[0030] Poloxamers have the general formula (I)

[0031] For different poloxamers numbers of x (PEO), y (PPO chain) and z (PEO) are varying over a broad range, depending on the type of poloxamer. For poloxamer P188 the PPO chain contains in the average a unit number ranging from 25 to 30, and each PEO is composed of 75 to 85 EO units in average, with a molecular weight ranging from 7680 to 9510 Da. For poloxamer P407 the PPO chain contains in the average a unit number of 56, and each PEO is composed of approximately 101 EO units in average, with an molecular weight ranging from 9840 to 14600 Da.

[0032] Poloxamer 407 (a=101 , b=56) with molecular weight ranging from 9840 to 14600 Da.

[0033] Table 1 is showing types of poloxamers monographed in the European Pharmacopoeia (Ph. Eur.) and United States Pharmacopeia (USP).

[0034] Table 1 Some poloxamers are commercially available at different ratios of EO and PO units and in different forms like liquids, pastes and wax-like solids, e.g. Synperonic® (Croda International PLC), Pluronic® (BASF SE), Lutrol® (BASF SE renamed in Kolliphor® and Kollisolv®) or Poloxamer 188 EMPROVE® EXPERT.

[0035] Alternatively, poloxamers can be made from raw materials according to methods known in the art (see, for example, II. S. Patent Nos. 3,579,465 and 3,740,421).

[0036] Further information about poloxamers can be found in Hagers Handbuch der Pharmazeutischen Praxis, 1994, or Russo, Villa, 2019.

[0037] Poloxamers according to the invention have a melting point of 20°C or higher.

[0038] In a further embodiment, poloxamers according to the invention have a melting point between 20°C and 60°C, between 30°C and 60°C, between 40°C and 60°C or between 50°C and 60°C. In a further embodiment, poloxamers according to the invention have an average molecular weight of 1500 Da or higher, between 1500 and 20000 Da, between 4000 and 15000 Da or between 7000 and 13000 Da. In a further embodiment, poloxamers according to the invention have a weight percentage of ethylene oxide chains between 40% and 90%, 50% and 90% or 70% and 85% .

[0039] In another embodiment the poloxamer is poloxamer P188, P237, P338, P407 or a mixture thereof. Preferably, the poloxamer is poloxamer P188 or P407.

[0040] In a further embodiment of the invention, the poloxamer can also be replaced by other components, such as polysorbates, polyoxyethylene fatty acid esters, sorbitan mono laureate, lecithin, phospholipids, sodium lauryl sulphate, cetrimide, alkyl betaine, d-a-tocopherol polyethylene glycol succinate, oleic and palmitic acid.

[0041] According to the invention, the term “hydrophilic binder” means a component that is used to transform powder into granules during a granulation process giving granules strength through adhesive properties. Dry binders can be added directly to the powder intended for direct compression to enhance compressibility of the powder and add mechanical strength to the final dosage form.

[0042] Suitable hydrophilic binder for use in the present invention include, but are not limited to natural and synthetic polymers and polysaccharides, e.g. gelatin, (pregelatinized) starch and agar or synthetic polymers, e.g. polyvinylpyrrolidone (PVP) , polyethyleneglycol (PEG), cellulose derivates (e.g. methyl cellulose, ethyl cellulose, sodium carboxymethyl cellulose, hydroxypropylmethyl cellulose, hydroxypropyl cellulose) or polyvinyl alcohol (PVA).

[0043] Preferably, the hydrophilic binder is polyvinyl alcohol.

[0044] Polyvinyl alcohol (PVA) is a synthetic water-soluble polymer that has the idealized formula [CH2CH(OH)]n. It possesses good film-forming, adhesive, and emulsifying properties. PVA is prepared from polyvinyl acetate, where the functional acetate groups are either partially or completely hydrolysed to alcohol functional groups. If not completely hydrolysed, PVA is a random copolymer consisting of vinyl alcohol repeat units -[CH2CH(OH)]- and vinyl acetate repeat units -[CH2CH(OOCCH3)]-. The polarity of PVA is closely linked to its molecular structure. The hydrolysis degree and the molecular weight determine the molecular properties of PVA. As the degree of hydrolysis of acetate groups increases, the solubility of the polymer in aqueous media and also crystallinity and melting temperature of the polymer increase. However, at high hydrolysis degrees over 88%, the solubility of PVA decreases again. PVA is generally soluble in water, but almost insoluble in almost all organic solvents, excluding, in some cases, ethanol.

[0045] The typical PVA nomenclature indicates the viscosity of a 4% solution at 20°C and the degree of hydrolysis of the polymer. For example, PVA 3-83 is a PVA grade with a viscosity of 3 mPas that is 83% hydrolysed, i.e. having 83% of vinyl alcohol repeat units and 17% of vinyl acetate repeat units. A skilled person is aware that a hydrolysis grade of 83% and a viscosity of 3 mPas encompasses calculated hydrolysis grades of 82.50% to 83.49% and calculated viscosities of 2.50 mPas to 3.49 mPas according to common rounding methods. Viscosity according to the invention is measured as stated in USP 39 under Monograph “Polyvinyl Alcohol” with the method Viscosity-Rotational Method (912). The degree of hydrolysis according to the invention is measured by determining the saponification value of the Polyvinyl Alcohol, e.g. as stated in USP 39 under Monograph “Polyvinyl Alcohol” under “Degree of Hydrolysis”:

[0046] Sample: 1 g of Polyvinyl Alcohol, previously dried at 110° to constant weight Analysis:

[0047] Transfer the Sample to a wide-mouth, 250-ml conical flask fitted by means of a suitable glass joint to a reflux condenser. Add 35 ml of dilute methanol (3 in 5) and mix gently to ensure complete wetting of the solid. Add 3 drops of phenolphthalein TS, and add 0.2 N hydrochloric acid or 0.2 N sodium hydroxide if necessary, to neutralize. Add 25.0 ml of 0.2 N sodium hydroxide VS, and reflux gently on a hot plate for 1 h. Wash the condenser with 10 ml of water, collecting the washings in the flask, cool, and titrate with 0.2 N hydrochloric acid VS. Concomitantly perform a blank determination in the same manner, using the same quantity of 0.2 N sodium hydroxide VS.

[0048] Calculation of saponification value: Calculate the saponification value:

[0049] Result = [(VB - VS) x N x Mr] / W

[0050] VB = volume of 0.2 N hydrochloric acid VS consumed in the titration of the blank (ml)

[0051] VS = volume of 0.2 N hydrochloric acid VS consumed in the titration of the Sample solution (ml)

[0052] N = actual normality of hydrochloric acid VS

[0053] Mr = molecular weight of potassium hydroxide, 56.11

[0054] W = weight of the portion of Polyvinyl Alcohol taken (g)

[0055] Calculation of degree of hydrolysis:

[0056] Calculate the degree of hydrolysis, expressed as a percentage of hydrolysis of polyvinyl acetate:

[0057] Result = 100 - [7.84 x S / (100 - 0.075 x S)) S = saponification value of the Polyvinyl Alcohol

[0058] According to the present invention the PVA grade PVA 3-82 refers to a PVA with the following specifications: pH: 5.0- 6.5

[0059] Viscosity: 2.55 - 3.45 Ester value: 180 - 220

[0060] The ester value IE according to Ph.Eur. 10.8 is the number that expresses in milligrams the quantity of potassium hydroxide required to saponify the esters present in 1 g of the substance. It is calculated from the saponification value Is and the acid value IA:

[0061] IE = Is - IA

[0062] The use of PVA grades according to the invention is of interest for the formulation of solid oral pharmaceutical dosage forms with an instant, immediate or prolonged API release.

[0063] Preferred PVAs have a hydrolysis degree of between 70% to 90%, more preferably between 74% to 88%. With regard to the viscosity of the PVA grades for the use according to the invention, in principle all PVA grades with a viscosity suitable for spray-drying are applicable for the spray-drying methods according to the invention. The skilled person in the art knows to select a PVA grade with a suitable viscosity for those methods. In a preferred embodiment the PVAs have a viscosity of a 4 % solution at 20° C of 20 mPas or lower, in a further preferred embodiment the PVAs have a viscosity of a 4 % solution at 20° C of between 1 to 18 mPas, in a further preferred embodiment the PVAs have a viscosity of a 4 % solution at 20° C of between 2 to 10 mPas, more preferably a viscosity of a 4 % solution at 20° C of between 2 to 5 mPas, most preferably a viscosity of a 4 % solution at 20° C of between 3 to 5 mPas. Preferably, the polyvinyl alcohol is PVA 3-80, PVA 3-81 , PVA 3-82 PVA 3-83, PVA 2-88, PVA 3-88, PVA 4-88, PVA 5-88, PVA 2-74, PVA 3-74, PVA 4-74 or PVA 5-74, more preferably PVA 3-82 or PVA 4-88, most preferably PVA 4-88.

[0064] According to the invention, the term "superdisintegrant" means a substance which is suitable for use in a solid-dose pharmaceutical formulation and which are typically incorporated to provide improved disintegration of the dosage form. Preferably, other properties, including but not limited to, compressibility, material flow, content uniformity, processing steps, and / or tablet size are maintained or improved. Suitable compression aids for use in the co-processed excipient composition of the invention include the synthetic superdisintegrants croscamellose sodium (CCS), sodium starch glycolate and crospovidone. Preferably, croscamellose sodium is used.

[0065] According to the invention, the term "lubricant" is intended to mean a non-polymeric substance which is suitable for use in a solid-dose pharmaceutical formulation and which reduces friction between moving parts during compression or compaction of the components of said pharmaceutical formulation.

[0066] Suitable compression aids for use in the co-processed excipient composition of the invention include fatty acids, metallic salts of fatty acids, metallic salts of hydrocarbons, metallic salts of fatty alcohols, fatty acid esters and alkyl sulfates. Preferably fatty acids, metallic salts of fatty acids or fatty acid esters, more preferably stearic acid or derivatives of stearic acid. Most preferably, stearic acid (STA), sodium stearyl fumarate (SSF) or magnesium stearate (MST) are used.

[0067] In a further embodiment of the invention the co-processed excipient composition for solid-dose pharmaceutical formulation, comprises a) from about 75 percent to 97 percent by weight of at least one filler, b) from about 1.5 percent to 5 percent by weight of at least one poloxamer, c) from about 0.2 percent to 5 percent by weight of at least one hydrophilic binder, d) from about 1 percent to 5 percent by weight of at least one superdisintegrant, and e) from about 0.2 percent to 5 percent by weight of at least one lubricant.

[0068] In a further embodiment of the invention the co-processed excipient composition for solid-dose pharmaceutical formulation, comprises a) from about 75 percent to 97 percent by weight of mannitol, b) from about 1 percent to 10 percent by weight of at least one poloxamer, c) from about 0.2 percent to 5 percent by weight of at least one hydrophilic binder, d) from about 1 percent to 5 percent by weight of at least one superdisintegrant, and e) from about 0.2 percent to 5 percent by weight of at least one lubricant.

[0069] In a further embodiment of the invention the co-processed excipient composition for solid-dose pharmaceutical formulation, comprises a) from about 75 percent to 97 percent by weight of at least one filler, b) from about 1 percent to 10 percent by weight of poloxamer P188 or P407, preferably poloxamer P188, c) from about 0.2 percent to 5 percent by weight of at least one hydrophilic binder, d)from about 1 percent to 5 percent by weight of at least one superdisintegrant, and e) from about 0.2 percent to 5 percent by weight of at least one lubricant.

[0070] In a further embodiment of the invention the co-processed excipient composition for solid-dose pharmaceutical formulation, comprises a) from about 75 percent to 97 percent by weight of at least one filler, b) from about 1 percent to 10 percent by weight of at least one poloxamer, c) from about 0.2 percent to 5 percent by weight of polyvinyl alcohol, preferably a polyvinyl alcohol has a hydrolysis degree of between 70% to 90% and a viscosity of a 4 % solution at 20° C of between 3 to 5 mPas, more preferably a polyvinyl alcohol selection from the list comprising PVA 3- 80, PVA 3-81 , PVA 3-82 PVA 3-83, PVA 2-88, PVA 3-88, PVA 4-88, PVA 5-88, PVA 2-74, PVA 3-74, PVA 4-74 or PVA 5-74, most preferably polyvinyl alcohol 4-88, most preferably PVA 4-88, d) from about 1 percent to 5 percent by weight of at least one superdisintegrant, and e) from about 0.2 percent to 5 percent by weight of at least one lubricant.

[0071] In a further embodiment of the invention the co-processed excipient composition for solid-dose pharmaceutical formulation, comprises a) from about 75 percent to 97 percent by weight of at least one filler, b) from about 1 percent to 10 percent by weight of at least one poloxamer, c) from about 0.2 percent to 5 percent by weight of at least one hydrophilic binder, d) from about 1 percent to 5 percent by weight of at least one superdisintegrant, selected from a group consisting of croscarmellose sodium, sodium starch glycolate and crospovidone, and e) from about 0.2 percent to 5 percent by weight of at least one lubricant.

[0072] In a further embodiment of the invention the co-processed excipient composition for solid-dose pharmaceutical formulation, comprises a) from about 75 percent to 97 percent by weight of at least one filler, b) from about 1.5 percent to 5 percent by weight of at least one poloxamer, c) from about 0.2 percent to 5 percent by weight of at least one hydrophilic binder, d) from about 1 percent to 5 percent by weight of at least one superdisintegrant, selected from a group consisting of croscarmellose sodium, sodium starch glycolate and crospovidone, and e) from about 0.2 percent to 5 percent by weight of at least one lubricant.

[0073] In a further embodiment of the invention the co-processed excipient composition for solid-dose pharmaceutical formulation, comprises a) from about 75 percent to 97 percent by weight of at least one filler, b) from about 1 percent to 10 percent by weight of at least one poloxamer, c) from about 0.2 percent to 5 percent by weight of at least one hydrophilic binder, d) from about 1 percent to 5 percent by weight of at least one superdisintegrant, and e) from about 0.2 percent to 5 percent by weight of at least one lubricant, selected from a group consisting of stearic acid, sodium stearyl fumarate and magnesium stearate.

[0074] In a further embodiment of the invention the co-processed excipient composition for solid-dose pharmaceutical formulation, comprises a) from about 75 percent to 97 percent by weight of mannitol, b) from about 1 percent to 10 percent by weight of a poloxamer, c) from about 0.2 percent to 5 percent by weight of polyvinyl alcohol, d) from about 1 percent to 5 percent by weight of at least one superdisintegrant, selected from a group consisting of croscarmellose sodium, sodium starch glycolate and crospovidone, and e) from about 0.2 percent to 5 percent by weight of at least one lubricant, selected from a group consisting of stearic acid, sodium stearyl fumarate and magnesium stearate.

[0075] In a further embodiment of the invention the co-processed excipient composition for solid-dose pharmaceutical formulation, comprises a) from about 75 percent to 97 percent by weight of mannitol, b) from about 1 percent to 10 percent by weight of a poloxamer, c) from about 0.2 percent to 5 percent by weight of polyvinyl alcohol, d) from about 1 percent to 5 percent by weight of at least one superdisintegrant, selected from a group consisting of croscarmellose sodium, sodium starch glycolate and crospovidone, and e) from about 0.2 percent to 5 percent by weight of at least one lubricant, selected from a group consisting of stearic acid, sodium stearyl fumarate and magnesium stearate.

[0076] In a further embodiment of the invention the co-processed excipient composition for solid-dose pharmaceutical formulation, comprises a) from about 75 percent to 97 percent by weight of mannitol, b) from about 1 percent to 10 percent by weight of a poloxamer P188 or P407, c) from about 0.2 percent to 5 percent by weight of polyvinyl alcohol PVA4-88, d) from about 1 percent to 5 percent by weight of croscarmellose sodium, and e) from about 0.2 percent to 5 percent by weight of at least one lubricant, selected from a group consisting of stearic acid, sodium stearyl fumarate and magnesium stearate.

[0077] In a further embodiment of the invention the co-processed excipient composition for solid-dose pharmaceutical formulation, comprises a) from about 75 percent to 97 percent by weight of mannitol, b) from about 1 percent to 10 percent by weight of poloxamer P188, c) from about 0.2 percent to 5 percent by weight of polyvinyl alcohol PVA4-88, d) from about 1 percent to 6 percent by weight of croscarmellose sodium, and e) from about 0.2 percent to 5 percent by weight of sodium stearyl fumarate.

[0078] In a further embodiment of the invention the co-processed excipient composition for solid-dose pharmaceutical formulation, comprises a) from about 75 percent to 97 percent by weight of mannitol, b) from about 1.5 percent to 5 percent by weight of poloxamer P188, c) from about 0.2 percent to 5 percent by weight of polyvinyl alcohol PVA4-88, d) from about 1 percent to 6 percent by weight of croscarmellose sodium, and e) from about 0.2 percent to 5 percent by weight of sodium stearyl fumarate.

[0079] In a further embodiment of the invention the co-processed excipient composition for solid-dose pharmaceutical formulation, comprises a) from about 85 percent to 95 percent by weight of mannitol, b) from about 1 percent to 5 percent by weight of poloxamer P188, c) from about 0.2 percent to 1 percent by weight of polyvinyl alcohol PVA4-88, d) from about 2 percent to 6 percent by weight of croscarmellose sodium, and e) from about 1 percent to 3 percent by weight of sodium stearyl fumarate.

[0080] In a further embodiment of the invention the co-processed excipient composition for solid-dose pharmaceutical formulation, comprises a) from about 86 percent to 94.3 percent by weight of mannitol, b) from about 2.5 percent to 4 percent by weight of poloxamer P188, c) from about 0.2 percent to 1 percent by weight of polyvinyl alcohol PVA4-88, d) from about 2 percent to 5 percent by weight of croscarmellose sodium, and e) from about 1 percent to 4 percent by weight of sodium stearyl fumarate.

[0081] In a further embodiment of the invention the co-processed excipient composition for solid-dose pharmaceutical formulation, comprises a) from about 88 percent to 93 percent by weight of mannitol, b) from about 2 percent to 4 percent by weight of poloxamer P188, c) from about 0.3 percent to 1 percent by weight of polyvinyl alcohol PVA4-88, d) from about 3 percent to 5 percent by weight of croscarmellose sodium, and e) from about 1 percent to 3 percent by weight of sodium stearyl fumarate.

[0082] In a further embodiment of the invention the co-processed excipient composition for solid-dose pharmaceutical formulation, comprises a) about 90.5 percent by weight of mannitol, b) about 3 percent by weight of poloxamer P188, c) about 0.5 percent by weight of polyvinyl alcohol PVA4-88, d) about 4 percent by weight of croscarmellose sodium, and e) about 2 percent by weight of sodium stearyl fumarate.

[0083] In a further embodiment of the invention the co-processed excipient composition for solid-dose pharmaceutical formulation, comprises a) 90.5 percent by weight of mannitol, b) 3 percent by weight of poloxamer P188, c) 0.5 percent by weight of polyvinyl alcohol PVA4-88, d) 4 percent by weight of croscarmellose sodium, and e) 2 percent by weight of sodium stearyl fumarate. In a further embodiment of the invention the co-processed excipient composition for solid-dose pharmaceutical formulation, consisting of a) 90.5 percent by weight of mannitol, b) 3 percent by weight of poloxamer P188, c) 0.5 percent by weight of polyvinyl alcohol PVA4-88, d) 4 percent by weight of croscarmellose sodium, and e) 2 percent by weight of sodium stearyl fumarate.

[0084] In a further embodiment of the invention the co-processed excipient composition for solid-dose pharmaceutical formulation, comprises a) 90.5 percent by weight of mannitol, b) 2 percent by weight of poloxamer P188, c) 0.75 percent by weight of polyvinyl alcohol PVA4-88, d) 4 percent by weight of croscarmellose sodium, and e) 2 percent by weight of sodium stearyl fumarate.

[0085] A further embodiment of the invention is a process for preparing a co-processed excipient composition according to the invention comprising a) combining the components of the co-processed excipient composition and b) co-processing the combined components to form a physically bound composite of the components.

[0086] Suitable co-processing methods include, but are not limited to, wet and dry granulation, fluidized bed granulation, spray granulation, spray drying, direct compression, roller compaction, melt extrusion, milling, surface adsorption, surface modification, dry coating, controlled crystallization or crystallo-coagglomeration. Preferably, the composition is co-processed by wet granulation or spray-drying, more preferably by spray-drying.

[0087] A further embodiment of the invention is a process for preparing a co-processed excipient composition according to the invention comprising a) adding components to the powder bed, b) dissolving components of the spray solution in an appropriate solvent and c) spray-granulating to form co-processed granules.

[0088] In one embodiment, the co-processing is a fluid bed granulation.

[0089] In one embodiment, the components added to the powder bed in step a) are the non-polymeric components of the co-processed formulation, preferably the at least one filler, superdisintegrant and lubricant. In one embodiment, the components dissolved in the spray solution in step b) are the polymeric components of the co-processed formulation, preferably the at least one poloxamer and hydrophilic binder.

[0090] In one embodiment, the appropriate solvent in step b) is water.

[0091] A further embodiment of the invention is the use of the co-processed excipient composition of the invention in the preparation of a solid-dose pharmaceutical formulation.

[0092] A further embodiment of the invention is a solid-dose pharmaceutical composition comprising the co-processed excipient composition according to the invention and an active pharmaceutical ingredient.

[0093] The active pharmaceutical ingredient (API) is a biologically active agent. The API may be a small molecule in form of a weak base, a weak acid or a neutral molecule and may be in the form of one or more pharmaceutically acceptable salts, esters, derivatives, analogues, prodrugs, and solvates thereof. The ASD of the present invention may comprise more than one API. In one embodiment the API is poorly soluble or a lipophilic API.

[0094] As used herein, the terms “poorly soluble API”, “poorly water-soluble API” and “lipophilic API” refer to an API having a solubility such that the highest therapeutic dose of the particular API to be administered to an individual cannot be dissolved in 250 ml of aqueous media ranging in pH from 1 to 8 following the definition of low solubility according to the Biopharmaceutics Classification System (BCS) classes 2 and 4. Poorly soluble APIs with weakly basic or weakly acidic characteristics have a pH-dependent solubility profile and can have a wide range of solubility in the aqueous environment of the gastrointestinal tract. APIs falling under BCS classes 2 or 4, respectively, are well known to persons skilled in the art.

[0095] In one embodiment the API is a weakly basic API. As used herein, the term “weakly basic API” refers to a basic active pharmaceutical ingredient (API) wherein the basic API does not completely ionize in water. The API included in the pharmaceutical dosage form of the present invention has a sufficient amount to be therapeutically effective. For a given API, therapeutically effective amounts are generally known or readily accessible by persons skilled in the art. Typically, the API may be present in the pharmaceutical dosage form in a weight ratio of API to co-processed excipient of 0.1 :99.1 to 60:40, preferably 1 :99 to 50:50, more preferably 5:95 to 40:60 and most preferably 10:90 to 30:70.

[0096] A further embodiment of the invention is a process for preparing a solid-dose pharmaceutical formulation comprising a) combining the co-processed excipient composition of the invention with an active pharmaceutical ingredient, b) blending the resulting combination until a homogenous blend is obtained and c) feeding the blend formed in step b) to an apparatus suitable for formation of the solid-dose pharmaceutical formulation.

[0097] In step a) of the process for preparing a solid-dose pharmaceutical formulation, optional conventional additives may be combined with the co-processed excipient composition and the active pharmaceutical ingredient. The optional conventional additives may include one or more of lubricants, sweetening agents, flavouring agents and the like.

[0098] Preferably, the solid-dose pharmaceutical formulation is a tablet and the apparatus in step c) is a tablet press.

[0099] It was surprisingly found that the co-processed excipient compositions of the present invention posess beneficial properties, in particular for solid-dose pharmaceutical formulation. The granulated material shows a homogeneous distribution of all individual components with a very good flowability facilitating powder handling. The particle size distribution and chemical nature of components leads to excellent tabletability generating tablets with optimal properties regarding tablet weight variation, tablet hardness, friability and disintegration. The ejection forces during tableting are very low emphasizing the lubrication effect. Surprinsingly, incorporating the lubricant into the granulated material and not in an external phase, did not result in loss of lubrication but had no effect on ejection forces. Examples:

[0100] Methods

[0101] The following methods were used to prepare and analyze the solid dosage forms in Examples 1 to 14.

[0102] 1. Co-processed granule manufacturing

[0103] Fluid bed granulation

[0104] The non-polymer components of the powder bed (filler, superdisintegrant and lubricant) are weighted and added to the compartment of the GEA fluidized bed spray granulator Multi-Processor MP1. The polymeric components of the spray solution (poloxamer and hydrophilic binder) are dissolved in water. The granulation process is performed at an inlet air temperature of 60°C and an inlet air volume of 30 m3 / h. The spray nozzle with a diameter of 0.8 mm is used in the position closest to the powder bed (position 1). The feed is forwarded at 9% rate of the peristaltic pump with a spray rate of 10 g / min and pressure of 800 mbar. During the process, the exhaust temperature ranges between 25 - 30 °C, during drying, it is held at 30 °C, during pre-heating at 40 °C. The final co-processed granules are sieved using a 1.0 mm sieve.

[0105] 2. Compression of tablets

[0106] Mixtures

[0107] API is added to the co-processed granule in the defined amount and the two- component system mixed for 5 minutes using a Turbula mixer.

[0108] For physical mixtures of non-co-processed components, all components except the lubricant are weighed into container and mixed for 5 minutes using a Turbula mixer. After the mixing time, the lubricant is added and again mixed for 5 minutes using a Turbula mixer.

[0109] Compression of tablets

[0110] Tablets are compressed using a Korsch one punch tablet press “Styl'One Evolution" with tablet weights of 500 mg. Tablets are round, 11.0 mm in diameter flat facetted. Compression forces of 5, 10, 15, 20 or 30 kN are used. The machine speed is set to 25 % for one compression. If not further described, tablets are compressed at 10 kN.

[0111] Measuring of tablet properties

[0112] Tablet properties are measured using the methods indicated in table 1.

[0113] Table 1

[0114] 3. Dissolution test

[0115] Dissolution is performed using a SOTAX AT7 smart (Apparatus 2, paddle; Ph. Eur.). All dissolution experiments are performed in media heated to 37 °C. Formulations were added as tablets after compression using 10 kN compression force. As comparative examples, the respective amounts of crystalline API (50 mg of Fenofibrate, 100 mg of Itraconazole, and 25 mg Indomethacin) were added to the dissolution medium without a further processing step. For Fenofibrate 1000 ml SGF + 0.1 % SDS, for Itraconazole 1000 ml SGF and for Indomethacin 900 mg SGF are used. At predetermined timepoints, an online UVA / is measurement is performed to calculate the content of API in the dissolution media. This UV wavelength is 290 nm for Fenofibrate, 260 nm for Itraconazole and 318 nm for Indomethacin.

[0116] Dissolution of Ibuprofen is performed following the USP Monograph of Ibuprofen ("Ibuprofen tablets” Volume No. 41(1), USP43-NF38-2285) for immediate release evaluation. 200 mg of crude Ibuprofen or the respective compressed Ibuprofen tablets are investigated.1000 ml of phosphate buffer pH 7.2 is used as dissolution media with a UV / Vis detection at 221 nm with 50 rpm.

[0117] Example 1

[0118] Mannitol with different particle size distributions (PSD) (Mannitol 1 and 2) (see table 2) and PVA 4-88 (PVA) as well as Mannitol and Poloxamer 188 (PLX188) were used in different co-processed excipient (CPE) compositions ranging from 1.5% - 3% PVA:Mannitol and 1-3% PLX188:Mannitol (Fig. 1). Additionally, the different Mannitol grades were investigated. Overall, tablet quality was insufficient for the coprocessed Mannitol + PLX188 samples especially regarding friability and tablet integrity. Within this combination, the highest PLX188 content exhibited the most promising qualities. The Mannitol + PVA samples exhibited average tablet quality with disintegration values around 600 seconds. Release studies showed slow disintegration when compressed with Ibuprofen as a model API. After 120 minutes of dissolution time, only 27 % of Ibuprofen were released (Fig. 2) therefore the addition of a disintegrant, the decrease of PVA content and an increase in Poloxamer content was investigated (see Example 2). To investigate lubrication efficacy of the used PLX188, no additional lubricant was added to the Mannitol + PLX188 samples before tableting (internal lubrication). For the PVA-based samples, external lubrication was achieved by mixing the co-processed components with Magnesium Stearate (MST) before tableting.

[0119] Table 2

[0120] Compositions used for Example 1 are shown in table 3 and 4: Table 3

[0121] Table 4

[0122] Example 2

[0123] A four-component system was designed using results from Example 1 with Mannitol as filler material: the PLX188 content investigated in concentrations of 3 - 5%, PVA was added as a binder in decreased amounts of 0.5% and 1% of croscarmellose sodium was added due to disintegration challenges with compositions of Example 1. Poloxamer was also investigated as a lubrication agent, therefore no other external lubrication was added when tablet compression was performed. While the ejection forces are within a good processing range, a sticking to the punches of the tablets indicate that the lubrication performance of PLX188 alone is not sufficient (Fig. 3).

[0124] Compositions used for Example 2 are shown in table 5:

[0125] Table 5

[0126] Example 3

[0127] The combination of Mannitol 1 + 1 % CCS + 0.5% PVA + 3% PLX188 showed the most favorite disintegration time 263 (seconds) of the compistion use for Example 2 and this candidate was further investigated regarding the performance over a greater variety of compression forces ranging from 10 to 30 kN. As it can be seen in Fig. 4, that increasing the compression force to > 10 kN leads to insufficient tablets that laminated during friability testing. This solidifies the need for additional lubrication.

[0128] Compositions used for Example 3 are shown in table 6:

[0129] Table 6

[0130] Example 4

[0131] In the following, a lubricant was added externally. Due to lamination of tablets during compression when adding an external lubricant, we determine that a lubricant needs to be investigated when added internally to the composition (Fig. 5). For this purpose, magnesium stearate (MST) and calcium stearate was investigated as external lubricants. MST was added to the spray solution as well as the powder bed during co-processing and the performance of the granules compared after tableting. The addition of MST to the spray solution results in a suspension that leads to clogging of the nozzle. Therefore the addition of MST to the powder bed was determined to be the method of choice. The qualities of tablets compressed from both formulations do not differ in performance (Example 6). de compositions used for Example 4 are shown in table 7 and 8:

[0132] Table 7

[0133] Table 8

[0134] Example 5

[0135] The optimal concentration of the super disintegrant was evaluated by varying the croscarmellose sodium (CCS) amount in concentrations ranging from 1.0 - 3.0 %. The performance of the tablets regarding ejection forces (Fig. 7), tablet hardness (Fig. 8) and disintegration (Fig. 9) were tested. The optimal CCS concentration was determined to be 2% for the composition comprising Mannitol 2 + 0.5 % PVA +3.0 % PLX188 + 0.5 % MST. While 3.0 % of CCS lead to high ejection forces, small amounts, such as 1.0 % lead to higher disintegration values especially at lower compression forces. The composition containing 3.0 % CCS showed enhanced characteristics in regard to tableting behavior.

[0136] Compositions used for Example 5 are shown in table 9:

[0137] Table 9

[0138] Example 6

[0139] In a further experiment, Mannitol and the lubricant, were exchanged and the behavior of the altered co-processed excipient investigated and compared to the compositions of Example 7.

[0140] Another grade of Mannitol, Mannitol 3 (see Table 2), was used. A higher CCS concentration was investigated due to the increased particle size of Mannitol 3.

[0141] Additionally, an alternative lubricant was investigated. Sodium Stearyl Fumerate (SSF) is a water soluble lubricant that was added to the powder bed in the same manner as MST was processed. The concentration of SSF was increased to receive a comparable performance to MST. The resulting composition, containing 4.0 % CCS, 2.0 % SSF, 0.5 % PVA and 3.0 % PLX188, was compared with Mannitol 2 vs. Mannitol 3 as filler. The results show a comparable behavior of the compressed tablets from both compositions (Fig. 10 and Fig. 11).

[0142] Compositions used for Example 6 are shown in table 10:

[0143] Table 10

[0144] Example 7

[0145] In a further experiment, the behavior of the granules in tableting was investigated when using a different Poloxamer grade. Therefore, PLX188 was exchanged by Poloxamer 407 (PLX407) and compared with two different Mannitol grades, Mannitol 2 and Mannitol 3. As seen in Fig. 11 and Fig. 12, both compositions show comparable behavior. Additionally, when comparing Fig. 10 and Fig. 11 versus Fig. 12 and Fig. 13, no significant difference between the performance of the granules in the tableting process of both Poloxamer grades can be determined.

[0146] Compositions used for Example 7 are shown in table 11 :

[0147] Table 11

[0148] Example 8

[0149] Using the Mannitol 3 grade and SSF as lubricant, different concentrations of the super disintegrant, ranging from 3.0 to 5.0 % CCS, were investigated regarding optimal performance. A decrease in disintegration time and a decrease of tablet hardness can be seen for increasing amounts of CCS while the overall performance of the whole concentration range leads to high quality tablets (Fig. 14 and Fig. 15).

[0150] Compositions used for Example 8 are shown in table 12:

[0151] Table 12

[0152] Example 9

[0153] Analogous experiments as described in Example 7 were conducted using stearic acid (STA) as alternative lubricant. As with SSF, STA concentration was targeted to be 2% in the final product. Lubrication performance between STA and SSF is comparable looking at the ejection forces at different compression forces (Fig. 14 versus Fig. 16). Disintegration does not differ in samples containing different concentrations of CCS (Fig. 17). All grades show high quality tablets with high tablet hardness and low ejection forces (Fig. 16).

[0154] Taking together the finding of the Examples, lubricants MST, STA or SSF can be exchanged without losing lubrication efficiency. The Mannitol source can vary in particle size distribution and CCS works as an efficient super disintegrant ranging from 2.0 to 5.0 % depending on the Mannitol particle size used. PLX188 and PLX407 can be exchanged without having an effect on tablet qualities, such as tablet hardness, ejection force and disintegration.

[0155] Compositions used for Example 9 are shown in table 13:

[0156] Table 13

[0157] Example 10

[0158] In a further experiment, the need of PVA in the granule composition was evaluated. PVA was left out of the manufacturing process and the tableting behavior of the granules investigated. To balance the missing polymer PVA, different PLX concentrations were investigated. Interestingly, increasing concentrations of the wetting agent PLX, lead to higher disintegration times (Fig. 19). Overall, tablet quality is slightly decreased without PVA in the composition with overall lower tablet hardness (Fig. 18 versus Fig. 16).

[0159] Compositions used for Example 10 are shown in table 14:

[0160] Table 14

[0161] Example 11

[0162] Analogous experiments as described in Example 10 were performed with SSF as lubricant. The results (Fig. 20 and Fig. 21) are similar to those from Example 10.

[0163] Compositions used for Example 11 are shown in table 15: Table 15

[0164] Example 12

[0165] To evaluate if this slight decrease in tablet quality without PVA will significantly impact tableting, a model API was used to evaluate a non placebo formulation. Without the addition of PVA to the co-processed excipient, tableting of 20% sucralose fine led to tablets with little tablet hardness. Comparing to the similar composition including more CCS, which is known to overall decrease tablet hardness, the composition without PVA show a decreased tablet hardness (table 16).

[0166] Table 16

[0167] *At 10 kN compression force

[0168] Example 13

[0169] A suitable composition was evaluated to be Mannitol 3 + 4 % CCS + 0.5 % PVA + 3.0 % PLX188 or PLX407 + 2.0 % SSF which was further investigated in dissolution experiments. It was found that this composition enhances drug release of poorly soluble drugs such as Fenofibrate (Fig. 22), Indomethacin (Fig. 23) and Itraconazole (Fig. 24) compared to the crystalline substance and a respective, optimized physical mixture (PM). All dissolution experiments were conducted in simulated gastric fluid (SGF) at pH 1.2. Additionally, other compositions such as Mannitol 2 + 2.0 % CCS + 0.5 % PVA + 3.0 PLX188 and 1.0 % MST were investigated regarding their dissolution performance. For all co-processed excipients, only the API was added and the tablets compressed.

[0170] Compositions used for Example 13 are shown in tables 17 to 22:

[0171] Table 17

[0172] Table 18

[0173] Table 19

[0174] Table 20

[0175] Table 21

[0176] Table 22

[0177] Example 14

[0178] In a further experiment, the dissolution of Ibuprofen was investigated regarding the immediate release. Therefore, Ibuprofen was compressed with the co-processed excipient and the dissolution determined following the USP protocol for Ibuprofen release (table 1). Within 30 minutes, 100 % of Ibuprofen are released when formulated with the co-processed excipient. Using the same source of Mannitol in a physical mixture, these values can only be reached after 100 minutes.

[0179] Compositions used for Example 14 are shown in tables 23 and 24:

[0180] Table 23

[0181] Table 24

[0182] References

[0183] Tranova, T., et al., Study of rheological and tableting properties of lubricated mixtures of co-processed dry binders for orally disintegrating tablets. Eur J Pharm Sci, 2022. 168: p. 106035.

[0184] Rojas, J., I. Buckner, and V. Kumar, Co-proccessed excipients with enhanced direct compression functionality for improved tableting performance. Drug Dev Ind Pharm, 2012. 38(10): p. 1159-70.

[0185] Tian, J.-L., Tian, X. Ke, Comparative evaluation of a co-processed self-lubricating excipient LubriTose SD as a direct compression vehicle. J. Drug Del. Sci. Tech., 2012. 22(6): p. 562-567.

[0186] Moreton, R.C., Excipients to the year 2025 - and beyond! J. Excipients and Food Chem., 2019. 10(2): p. 29-40.

Claims

Claims1. A co-processed excipient composition for solid-dose pharmaceutical formulation, the composition comprising a) from about 75 percent to 97 percent by weight of at least one filler, b) from about 1.5 percent to 5 percent by weight of at least one poloxamer, c) from about 0.2 percent to 5 percent by weight of at least one hydrophilic binder, d) from about 1 percent to 5 percent by weight of at least one superdisintegrant, and e) from about 0.2 percent to 5 percent by weight of at least one lubricant.

2. A composition according to Claim 1, wherein the filler is mannitol.

3. A composition according to Claims 1 or 2, wherein the poloxamer is P188 or P407.

4. A composition according to any of Claims 1 to 3, wherein the hydrophilic binder is a polyvinyl alcohol.

5. A composition according to Claim 4, wherein the polyvinyl alcohol has a hydrolysis degree of between 70% to 90% and a viscosity of a 4 % solution at 20° C of between 3 to 5 mPas.

6. A composition according to any of Claims 1 to 5, wherein the superdisintegrant is selected from a group consisting of croscarmellose sodium, sodium starch glycolate and crospovidone.

7. A composition according to any of Claims 1 to 6, wherein the lubricant is selected from a group consisting of stearic acid, sodium stearyl fumarate and magnesium stearate.

8. A composition according to any of Claims 1 to 7 comprisinga) from about 75 percent to 97 percent by weight of mannitol, b) from about 1 .5 percent to 5 percent by weight of a poloxamer, c) from about 0.2 percent to 5 percent by weight of polyvinyl alcohol, d) from about 1 percent to 5 percent by weight of at least one superdisintegrant, selected from a group consisting of croscarmellose sodium, sodium starch glycolate and crospovidone, and e) from about 0.2 percent to 5 percent by weight of at least one lubricant, selected from a group consisting of stearic acid, sodium stearyl fumarate and magnesium stearate.

9. A composition according to any of Claims 1 to 8 comprising a) from about 86 percent to 94.3 percent by weight of mannitol, b) from about 2.5 percent to 4 percent by weight of poloxamer P188, c) from about 0.2 percent to 1 percent by weight of polyvinyl alcohol PVA 4-88, d) from about 2 percent to 5 percent by weight of croscarmellose sodium, and e) from about 1 percent to 4 percent by weight of sodium stearyl fumarate.

10. A composition according to any of Claims 1 to 9, wherein the composition is a spray-dried co-processed excipient composition.

11. A process for preparing a co-processed excipient composition according to any of Claims 1 to 10 comprising a) combining the components of the co-processed excipient composition and b) co-processing the combined components to form a physically bound composite of the components.

12. A process for preparing a co-processed excipient composition according to Claim 11 comprising a) adding components to the powder bed, b) dissolving components of the spray solution in an appropriate solvent andc) spray- granulating to form co-processed granules.

13. Use of the co-processed excipient composition according to any of Claims 1 to 10 in the preparation of a solid-dose pharmaceutical formulation.

14. A solid-dose pharmaceutical formulation comprising a composition according to any of Claims 1 to 10 and an active pharmaceutical ingredient.

15. A process for preparing a solid-dose pharmaceutical formulation according to Claim 14 comprising a) combining the co-processed excipient composition of the invention with an active pharmaceutical ingredient, b) blending the resulting combination until a homogenous blend is obtained, and c) feeding the blend formed in step b) to an apparatus suitable for formation of the solid-dose pharmaceutical formulation.

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