Coated tablet formulation and method

The present invention relates to a preparation in the form of a coated tablet which comprises a tablet core coated with an inhibitor of DPP4, which is saxagliptin or a pharmaceutically acceptable salt thereof, and a process for the preparation of such a preparation in the form of a coated tablet.

BACKGROUND OF THE INVENTION [0002] A compound with structure

<img file="PL2298288T3_D0001.tif" />

or a salt thereof with HCl, (hereinafter the above DPP4 inhibitor or saxagliptin) is an orally active reversible inhibitor of dipeptidyl peptidase 4 (DPP4) which is a therapeutic agent for the treatment of type 2 diabetes as disclosed in US Patent No. 6,395,767.

[0003] After ingestion of the meal, the insulinotropic hormone GLP-1 is released, which in turn causes the release of insulin from the pancreas. A certain amount of GLP-1 is inactivated by DPP4 present in blood plasma and intestinal vascular endothelium. Thus, if DPP4 is inhibited, more GLP-1 will be available to activate insulin released from the pancreas. The advantage of this mechanism of insulin release is that insulin is secreted only as a reaction to a meal. Thus, hypoglycaemic problems associated with other diabetes medicines will be less likely when using a DPP4 inhibitor.

[0004] The above DPP4 inhibitor is a labile compound that is prone to intramolecular cyclization as shown below.

<img file="PL2298288T3_D0002.tif" />

Cyclic Amidine Formation (CA) [0005] The resulting degradation product, a cyclic amidine (mainly cis-cyclic amidine (CA)), is not therapeutically active, and thus its formation is undesirable. This cyclization reaction can take place both in the solid state and in the solution. The rate of intramolecular cyclisation is accelerated when the formulations used are subjected to ordinary processing operations such as wet granulation, rolling or tableting. In addition, the most commonly used excipients, when mixed with this compound, can accelerate the rate of cyclization. In addition, the level of cis-cyclic amidine increases when the ratio of drug to excipient increases, posing more challenges for low-power dosage forms. Because of these properties of the molecule,

[0006] Currently, capsule formulations comprising a DPP4 inhibitor dry mix and commonly used excipients are produced on a small scale and used in clinical trials. Increasing the production scale of capsule formulations containing a DPP4 inhibitor will also be problematic in that it will require milling to control the particle size of the DPP4 inhibitor so that the lower strength capsules are produced without problems related to the uniformity of the composition.

[0007] In addition, most of the therapeutic agents as single units or as a combination product for the treatment of diabetes are available in a dosage form as tablets. Because the dosage form as a tablet is not feasible for a DPP4 inhibitor using conventional manufacturing methods, its production with other therapeutic agents as a combined tablet will be even more problematic. [0008] Thus, it is evident that there is clearly a need to develop stable pharmaceutical formulations comprising drugs that undergo intramolecular cyclisation resulting in the formation of degradation products, such as cyclic amidines that are not therapeutically active.

[0009] In US Patent No. 6,395,767 to Robl et al. (hereinafter, Robl et al) discloses dipeptidyl peptidase IV inhibitors based on pyrrolidine condensed with cyclopropyl (inhibitors)

DPP4), which include compounds of structure

<img file="PL2298288T3_D0003.tif" />

or

<img file="PL2298288T3_D0004.tif" />

or a pharmaceutically acceptable salt thereof, wherein the pharmaceutically acceptable salt may be a trifluoroacetic acid hydrochloride or salt.

[0010] Robl et al. disclose that DPP4 inhibitors including those given above can be formulated in the form of tablets, capsules, granules or powders.

[0011] WO 03/059330 describes pharmaceutical compositions comprising a core coated with a layer of ACE inhibitor (s).

BRIEF SUMMARY OF THE INVENTION [0012] A coated tablet according to the present invention is provided that may contain a drug that undergoes intramolecular cyclisation, but is surprisingly stable under normal storage conditions, i.e. at 30 ° C and 60% relative humidity.

[0013] The coated tablet according to the invention comprises a tablet core (also referred to as a "core", "tablet core", "placebo", "core tablet placebo", "tablet core composition" or "core composition") and

a) a coating layer coated on the core, which coating layer is an inner sealing coating;

b) a second coating layer, disposed on the inner seal coat, the second coating layer comprising a medicament which is saxagliptin or a pharmaceutically acceptable salt thereof, and wherein the second coating layer consists of from 0.1 to 70% by weight of the drug and from 30 to 99.5% by weight of the coating polymer, based on the weight of the second coating layer; and

c) an outer protective coating layer, placed on the second coating layer.

[0014] The drug is a DPP4 inhibitor with structure

<img file="PL2298288T3_D0005.tif" />

or a pharmaceutically acceptable salt thereof, such as a salt with HCl, also referred to as Compound A.

[0015] The coated tablet according to the invention comprises a tablet core,

a) an inner sealing coating layer which comprises a coating polymer formulation that comprises a poly (vinyl alcohol)-based polymer (PVA) and a plasticizer;

b) a second coating layer disposed on the sealing coating layer a) which comprises a medicament which is saxagliptin or a pharmaceutically acceptable salt thereof and a coating polymer formulation comprising a PVA-based polymer, and preferably the same polymer as the coating polymer of the inner sealing layer and plasticizer; and

c) an outer protective coating layer coated on a second coating layer of the tablet core, said outer protective coating layer comprising a coating layer formulation comprising a PVA-based polymer and a plasticizer.

[0016] The above coating layers are applied to the core of the tablet preferably by coating by spraying onto the core of the tablet.

[0017] The outer protective or third coating layer will be coated on a second coating layer (containing the drug) and will act as a protective layer. The third or protective coating layer may preferably contain similar components to the second coating layer, with the exception that it will not contain the drug, but may optionally contain one or more coloring agents, and does not necessarily contain the same amounts of such ingredients. Alternatively, a fourth layer (which contains similar components to the third layer) containing colorants and a coating polymer to vary the tablets of different strengths can also be applied. The first, second, third and fourth coating layers can be made to contain the same coating polymers.

[0018] It has been found that coated tablets according to the invention show improved chemical stability compared to conventional tablets made using conventional dry granulation or wet granulation techniques.

[0019] The coating approach will also facilitate the preparation of a combination drug problem with another drug by using another drug tablet as a starting tablet (instead of the tablet or placebo core mentioned above) and applying an inner seal coat and a second coating containing a problem drug and a coating polymer, and outer protective coating on another medicine tablet.

[0020] Coated tablets according to the invention can be prepared preferably using a perforated pan coater. Fluid bed coating and spray coating can also be used.

[0021] Furthermore, according to the present invention, there is provided a method of making a coated tablet according to the invention, which method comprises the steps of

a) providing the tablet core;

b) coating the tablet with an internal seal coat formulation that contains at least one PVA-based polymer and a plasticizer;

c) drying the coated tablet to form an inner sealing coat thereon;

d) coating the coated tablet with a second coating layer formulation that comprises a medicament which is saxagliptin or a pharmaceutically acceptable salt thereof and at least one PVA based coating polymer and a plasticizer;

e) drying the thus coated tablet to form a second coating layer thereon;

f) coating the coated tablet with a preparation of a third outer protective coating layer that comprises at least one PVA based coating polymer and a plasticizer; and

g) optionally, coating the coated tablet with a fourth outer protective coating layer which comprises at least one coating polymer and a coloring agent, and

h) drying the thus coated tablet to form a coated tablet according to the invention.

[0022] In a preferred embodiment of the method according to the invention, each of the inner preparation of the sealing coat layer, the second coating layer formulation and the preparation (s) of the outer protective layer (s) / layer (s) will be applied as a suspension coating polymer in coating solvent.

[0023] The third and fourth outer protective coating layer need not contain the drug (although they may, if desired), and they can be formulated from other components of the first coating layer and / or the second coating layer. The second coating layer may be formed from the components of the first coating layer and / or the third / and or fourth skin layer, but not necessarily from the same amounts of these components.

[0024] In the preparation of a coated tablet according to the invention, coating suspensions which contain the coating polymer in water are prepared. Other coating solvents that can be used include ethanol, methanol and isopropyl alcohol, with water being preferred. The tablets, which are a placebo (do not contain the drug) and form the tablet cores are coated with a suspension of the inner sealing coating and dried. The suspension of the second coating layer containing the drug and the coating polymer is applied to the tablets thus coated, which are then dried.

[0025] The coated tablet according to the invention is intended to comprise an outer protective layer for which a coating suspension is prepared as in the case of a suspension of the inner seal coat, but without the drug. The coating suspension is then coated with the previously coated tablets as described for the inner sealing coat and the second coating to form a protective coating layer thereon.

[0026] Coated tablets according to the invention are useful in the treatment of type II diabetes in mammals such as humans, dogs and cats.

DETAILED DESCRIPTION OF THE INVENTION [0027] The tablet or placebo core used in the coated tablet of the invention will contain conventional pharmaceutical excipients to allow the formation of a pharmaceutically acceptable solid tablet core. The core of the tablet may be in the form of tablets, beads, beads or pills, all of which are collectively referred to as the core of the tablet.

[0028] The coated tablet according to the invention will contain a medicament which is a DPP4 inhibitor, saxagliptin, in an amount ranging from about 0.1 to about 70% by weight, preferably from about 1 to about 50% by weight of the tablet core.

[0029] The tablet core used in the coated tablet according to the invention will preferably contain

a) at least one bulking agent or filler;

b) optionally at least one binder;

c) optionally at least one disintegrant; and

d) preferably but optionally at least one lubricant.

wherein

a) the bulking agent or filler is present in an amount ranging from about 1 to about 95% by weight, preferably from about 10 to about 85% by weight;

b) the binder is present in an amount ranging from about 0 to about 20% by weight, preferably from about 1 to about 10% by weight;

c) the disintegrant is present in an amount ranging from about 0 to about 20% by weight, and preferably from about 0.25 to about 10% by weight; and

d) the lubricant is present in an amount ranging from about 0 to about 5% by weight, preferably from about 0.2 to about 2% by weight, all of the above% by weight being given relative to the weight of the tablet core. [0030] It is preferred that the fillers are microcrystalline cellulose and lactose monohydrate;

the disintegrant was croscarmellose sodium; and the lubricant was magnesium stearate.

[0031] The tablet cores present in the coated tablets of the present invention can be prepared in various ways and with different orders of addition of excipients. The utility of these formulations is not limited to a particular dosage form or production method. The tablet cores may be made by wet granulation, dry granulation, direct mixing or any other pharmaceutically acceptable method.

[0032] According to the present invention, there is provided a preferred method for manufacturing tablet cores used in the case of coated tablets according to the invention, which comprises the steps of mixing one or more excipients, such as a bulking agent, an optional binder and optionally a disintegrant. Preferably, a lubricant will be added to the mixture to facilitate the preparation of the tablet.

The fillers or fillers will be present in tablet core compositions of the invention in an amount ranging from about 1 to about 95% by weight, and preferably from about 10 to about 85% by weight of the core composition. Examples of bulking agents or fillers suitable for use herein include, but are not limited to, cellulose derivatives such as microcrystalline cellulose or wood cellulose, lactose, sucrose, starch, pre-gelatinized starch, dextrose, mannitol, fructose, xylitol, sorbitol, starch. maize, modified corn starch, inorganic salts such as calcium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, dextrin / dextranes, maltodextrin, sugars suitable for compression, and other known bulking agents or fillers,

[0034] The binder will optionally be present in the pharmaceutical compositions of the invention in an amount ranging from about 0 to about 20% by weight, preferably from about 1 to about 10% by weight of the core composition. Examples of binders suitable for use herein include, but are not limited to, hydroxypropylcellulose, maize starch, pre-gelatinized starch, modified corn starch, poly (vinylpyrrolidone) (PVP) (MW in the range of about 5,000 to about 1,000,000, preferably about 40,000), hydroxypropyl methylcellulose (HPMC), lactose, gum arabic, ethylcellulose, cellulose acetate, as well as a wax binder such as carnauba wax, paraffin, spermaceti, polyethylene wax or microcrystalline wax,

[0035] The disintegrant will optionally be present in the pharmaceutical composition of the invention in an amount ranging from about 0 to about 20% by weight, preferably from about 0.25 to about 10% by weight of the core composition. Examples of disintegrants suitable for use herein include, but are not limited to, croscarmellose sodium, crospovidone, starch, potato starch, pre-gelatinized starch, corn starch, sodium starch glycolate, microcrystalline cellulose, low-substituted hydroxypropylcellulose, or other known agent. disintegrant, preferably croscarmellose sodium.

[0036] The lubricant will optimally be present in the pharmaceutical composition of the invention in an amount ranging from about 0.1 to about 5% by weight, preferably from about 0.2 to about 2% by weight of the core composition. Examples of tabletting lubricants suitable for use herein include, but are not limited to, magnesium stearate, zinc stearate, calcium stearate, talc, carnauba wax, stearic acid, palmitic acid, sodium stearyl fumarate, or hydrogenated vegetable oils and fats, or other tabletting lubricants, and / or a mixture of two or more thereof, preferably magnesium stearate.

[0037] The preparation of the inner sealing layer (also referred to as the first coating layer) will contain up to 95% of the polymer relative to the internal weight of the sealing coat layer and can be produced as described herein before. The formulation will contain at least one polymer coating layer and a coating solvent as described above, which is preferably water which is used for the production and is removed by drying. The coating layer comprises a polymer based on polyvinyl alcohol (PVA), preferably PVA. The coating layer also includes a plasticizer such as triacetin, diethyl phthalate, tributyl sebacate or polyethylene glycol (PEG), preferably PEG; and optionally an anti-sticking agent or a lubricant such as talc, pyrogenic silica or magnesium stearate, an opacifying agent such as titanium dioxide. The coating layer may also contain coloring agents based on iron oxide. Coating material is commercially available under the trade name Opadry® HP or Opadry® II white.

The preparation of the second coating layer will preferably be similar in composition to the first coating layer formulation, although it will contain a drug, preferably a DPP4 inhibitor in an amount ranging from about 0.5 to about 70%, preferably from about 30 to about 50% by weight, relative to the weight of the second coating layer.

[0039] The third outer protective coating layer will preferably be similar in composition to the first coating layer.

[0040] The fourth coating layer, when present, will preferably be similar in composition to the third outer protective coating layer and will contain the desired colorant as required, such as in an amount ranging from about 0.5 to about 5.0% by weight, relative to the weight of the fourth coating layer.

[0041] The inner sealing layer will preferably consist of a polymer of the coating layer in an amount ranging from about 10 to about 95%, preferably from about 20 to about 90% by weight of the inner sealing layer of the plasticizer in an amount in the range of about 10 to about 30%, preferably from about 15 to about 20% by weight of the coating layer and optionally the release agent or glidant in an amount ranging from about 15 to about 30%, preferably from about 10 to about 15% by weight of the inner sealing layer.

[0042] The second coating layer will preferably consist of a polymer of the coating layer in an amount ranging from about 30 to about 99.5%, preferably from about 40 to about 60% by weight of the second coating layer and the drug in an amount ranging from about 0.25 % to about 70%, preferably from about 20 to about 50% by weight of the second coating layer.

[0043] The polymer of the coating layer in the second coating layer will be present in an amount of at least about 5 mg for 200 mg of the tablet core and the drug will be present in an amount of at least about 0.5 mg.

[0044] The third outer protective coating layer will preferably be similar in composition to the first coating layer.

[0045] The inner sealing coat layer will be present in an amount ranging from about 1 to about 5%, preferably from about 1 to about 3% by weight of the final coated tablet; the second coating layer (containing the drug) will be present in an amount ranging from about 0.25 to about 70%, preferably from about 1 to about 50% by weight of the final coated tablet, depending on the strength; and each of the third outer protective coating layer and the fourth layer, when present, will be present in an amount ranging from about 1 to about 10%, preferably from about 1 to about 5% by weight of the final coated tablet.

[0046] Preferred formulated tablet formulations according to the invention are given below.

<td>Placebo tablet material</td><td>Possible range% / mg by weight 200 mg placebo tablet core</td><td>The preferred range is% / mg by weight 200 mg of the placebo tablet core</td>

<td>Filling agent</td><td>2 to 95% / 4 to 190 mg</td><td>10 to 85% / 20 to 170 mg</td>

<td>Lactose</td><td>0 to 95% / 0 to 190 mg</td><td>20 to 75/40 to 150 mg</td>

<td>Microcrystalline cellulose</td><td>0 to 95% / 0 to 190 mg</td><td>20 to 75% / 40 to 150 mg</td>

<td>Disintegrant</td><td>0 to 20% / 0 to 40 mg</td><td>0.25 to 10% / 0.5 to 20 mg</td>

<td>Croscarmellose sodium</td><td>0 to 20% / 0 to 40 mg</td><td>2 to 10% / 4 to 20 mg</td>

<td>Lubricant</td><td>0.1 to 5% / 0.2 to 10 mg</td><td>0.2 to 2% / 0.4 to 4 mg</td>

<td>Magnesium stearate</td><td>0.1 to 5% / 0.2 to 10 mg</td><td>0.2 to 2% / 0.4 to 4 mg</td>

<td>The first inner sealing coating layer</td><td>% / mg by weight 200 mg of the placebo tablet core</td><td>% / mg by weight 200 mg of the placebo tablet core</td>

<td>Coating polymer and plasticizer and optional lubricants</td><td>0.5 to 50% / 1 to 100 mg</td><td>1 to 3% / 2 to 6 mg</td>

<td>The second coating layer</td><td>% / mg by weight 200 mg of the placebo tablet core</td><td>% / mg by weight 200 mg of the placebo tablet core</td>

<td>saxagliptin (free base or salt with HCl)</td><td>0.1 to 70% / 0.2 to 140 mg</td><td>1 to 50% / 2 to 100 mg</td>

<td>The coating polymer and optional plasticizer and optional lubricants</td><td>1 to 70% / 2 to 140 mg</td><td>1 to 50% / 2 to 100 mg</td>

<td>Third outer protective coating layer</td><td>% / mg by weight 200 mg of the placebo tablet core</td><td>% / mg by weight 200 mg of the placebo tablet core</td>

<td>A coating polymer and optional plasticizer, optional lubricants and a dye</td><td>0.5 to 50% / 1 to 100 mg</td><td>1 to 5% / 2 to 10 mg</td>

[0047] The following Embodiment represents a preferred embodiment of the invention.

EXAMPLE [0048] A 500 g batch of 2.5 mg DPP4 coated tablets having the following composition was prepared as described below

<td>The core of the tablet</td><td>Weight (mg) Wt.% 200 mg of the placebo tablet core</td>

<td>NF lactose monohydrate</td><td>99 mg (49.5%)</td>

<td>Microcrystalline cellulose NF</td><td>90 mg (45%)</td>

<td>Croscarmellose sodium NF</td><td>10 mg (5%)</td>

<td>Magnesium stearate NF</td><td>1 mg (0.5%)</td>

<td>Whole</td><td>200 mg (100.0%)</td>

<td></td><td></td>

<td>Inner sealing coat layer</td><td>4 mg (2%)</td>

<td>Opadry® HP, which contains the following components</td><td></td>

<td>Poly (vinyl alcohol) 40%</td><td></td>

<td>PEG 20%</td><td></td>

<td>Talc 15%</td><td></td>

<td>Titanium dioxide 25%</td><td></td>

<td></td><td></td>

<td>Middle Layer</td><td></td>

<td>DPP4 inhibitor, Saxagliptin</td><td>2.5 mg (1.25%)</td>

<td>Opadry® HP</td><td>20 mg (10%)</td>

<td></td><td></td>

<td>External protective layer</td><td></td>

<td>Opadry® HP</td><td>4 mg (2%)</td>

[0049] 500 g tablet cores were prepared as follows.

[0050] Lactose monohydrate, croscarmellose sodium and microcrystalline cellulose were mixed in a planetary mixer. The blended magnesium stearate was then added to the blend as a lubricant and the blend was mixed using a Turbula blender.

The lubricant blend was then compressed using a single station press or a rotary press in a 200 mg placebo tablet.

Inner sealing coating layer [0051] A suspension of the inner sealing coating was prepared as follows.

[0052] 0.1 N HCl (about 226.7 g) in a metal tank was mixed continuously using a diminishing mixer. 40 g of Opadry® HP powder was quickly added to the vortex. After the addition of the powder was completed, stirring was continued at low speed until a homogeneous mixture was obtained. The pH of the resulting suspension was measured and the pH was adjusted to 2 using concentrated HCl or NaOH.

[0053] Glatt Coating was set according to the following parameters

<td colspan="2">Glatt coater parameter</td>

<td>The pumping speed</td><td>3.5-5 ml / min</td>

<td>Speed ​​of panwi</td><td>20 rpm</td>

<td>Air pressure</td><td>1.5 bar</td>

<td>The temperature of the air at the inlet</td><td>50 ° C</td>

<td>The temperature of the air being removed</td><td>around 38 ° C</td>

<td>Air flow</td><td>80 m³/hour</td>

<td>Distance of the nozzle from the bed</td><td>6.5 inches</td>

<td>The size of the nozzle</td><td>0.8 mm</td>

[0054] The tablet cores were pre-heated in a coating pan in about 10 to 15 minutes. 30 heated tablets were weighed. The drying of the tablets was continued until the moisture was removed from the tablet, and the weight of the tablet became unchanged. The final mass of 30 tablets is marked as A.

[0055] 30 tablets were coated with a suspension of an inner seal coat as prepared above using a Glatt coater.

[0056] 30 tablets were weighed every 10 minutes (and the mass was recorded) until the tablets reached the target mass (Equation 1). The coated tablets were dried by heating until the mass of the tablet remained unchanged. The final weight of the coated tablets was marked as B.

Equation 1:

Target mass = A x 1.02 = B

Middle (Drug) coating layer [0057] A suspension of the middle coating drug drug was prepared as follows.

[0058] To 1000 ml of 0.1 N HCl in a metal reservoir was added 12.5 g of DPP4 inhibitor (free base). The pH was measured and adjusted to 2. HCl was continuously stirred and 100 g of Opadry® HP was quickly added to the vortex. The mixture was then mixed at low speed until a homogeneous mixture was obtained. The pH of the slurry was maintained at level 2 using either concentrated HCl or 1N HCl as needed.

[0059] The cores of the tightly coated tablet prepared above were coated with the above-prepared coating suspension containing the DPP4 inhibitor using a coater

Glatt. 30 Coated tablets were weighed initially every 30 minutes and then every 15 minutes and the mass was recorded until the tablets reached the target mass (Equation 2). The thus coated tablets were dried by heating until the mass of the tablet remained unchanged. The final weight of 30 tablets is designated as C.

Equation 2:

Target weight =

B + 30 x (2.925 (equivalent to 2.5 mg free base) + 20 mg) = B + 6875 mg = C [0060] The amount of drug coated on the tablets was determined by HPLC, fiber optic probe, or NIR or other suitable techniques. The coating was terminated when the target amount of drug was embedded.

Outer protective coating layer [0061] The thus coated tablets were then coated with a Opadry® HP suspension which was used to form an inner sealing coat. 30 tablets were weighed every 10 minutes and the mass was recorded until the tablets reached the target mass (Equation 3). The tablets were dried by heating until the weight of the tablet remained unchanged.

[0062] The final weight of 30 tablets is designated as D.

Equation 3:

Target weight = C + 30 x 4 mg = C + 120 mg = D [0063] The thus coated tablets were transferred to a suitable container.

[0064] The tablets of the invention thus prepared had improved stability compared to conventional tablet formulations (in which the drug was in the core) and capsule formulations.

[0065] The above 2.5 mg film-coated tablets according to the invention were stored under various storage conditions up to and including 41 weeks and data for stability regarding the presence of cyclic amidine degradation product (mainly cis -cyclic amidine (Cis-CA) were collected. )). As shown in Table 1 below, no cis-CA was detected at storage conditions of 25 ° C / 60% RH. The cis-CA levels were 0.22% and 0.32%, respectively, under storage conditions of 30 ° C / 60% RH and 40 ° C / 75% RH. These levels are significantly lower than those observed for the 5 mg and 20 mg capsule formulations as shown in Table 2.

TABLE 1

<td colspan="19">Durability data after twenty-six weeks for a 2.5 mg tablet coated with Opadry^® HP, free base as starting material and three coating layers. To determine stability, the tablets were packed in HDPE bottles.</td>

<td>Conditions storage</td><td colspan="3">2 weeks for everyone closed conditions</td><td colspan="3">4 weeks for everyone closed conditions 1 week for two open conditions</td><td colspan="3">8 weeks for everyone closed conditions 5 weeks for two open conditions</td><td colspan="3">12 weeks for everyone closed conditions</td><td colspan="3">26 weeks for everyone closed conditions</td><td colspan="3">41 weeks for everyone closed conditions</td>

<td></td><td>% amide</td><td>% CISC</td><td>% TransCA</td><td>% amide</td><td>% Cis-CA</td><td>% TransCA</td><td>% amide</td><td>% Cis-CA</td><td>% TransCA</td><td>% amide</td><td>% Cis-CA</td><td>% TransCA</td><td>% amide</td><td>% Cis-CA</td><td>% TransCA</td><td>% amide</td><td>% Cis-CA</td><td>% TransCA</td>

<td>5 C-closed</td><td>0</td><td>0</td><td>0</td><td>0</td><td>0</td><td>0</td><td>0</td><td>0</td><td>0</td><td>0</td><td>0</td><td>0</td><td>0</td><td>0</td><td>0</td><td>0</td><td>0</td><td>0</td>

<td>25 ° C / 60% RH-closed</td><td>0</td><td>0</td><td>0</td><td>0</td><td>0</td><td>0</td><td>0</td><td>0</td><td>0</td><td>0</td><td>0</td><td>0</td><td>0</td><td>0</td><td>0</td><td>0.03</td><td>0</td><td>0</td>

<td>30 ° C / 60% RH-closed</td><td>0</td><td>0</td><td>0</td><td>0</td><td>0</td><td>0</td><td>0</td><td>0</td><td>0</td><td>0</td><td>0</td><td>0</td><td>0</td><td>0.22</td><td>0</td><td>0.03</td><td>0.17</td><td>0</td>

<td>40 ° C / 75% RH-closed</td><td>0</td><td>0</td><td>0</td><td>0</td><td>0.05</td><td>0</td><td>0</td><td>0.09</td><td>0</td><td>0</td><td>0.20</td><td>0.05</td><td>0</td><td>0.32</td><td>0</td><td>0.03</td><td>0.90</td><td>0</td>

<td>50 C-closed</td><td>0</td><td>0.17</td><td>0</td><td>0</td><td>0.33</td><td>0.15</td><td>0</td><td>0.52</td><td>0.12</td><td>0</td><td>0.75</td><td>0.15</td><td>0</td><td>1.00</td><td>0</td><td>0</td><td>1.62</td><td>0</td>

<td>30 ° C / 60% RH-open</td><td>ON</td><td>ON</td><td>ON</td><td>0</td><td>0</td><td>0</td><td>0</td><td>0.20</td><td>0.06</td><td>ON</td><td>ON</td><td>ON</td><td>ON</td><td>ON</td><td>ON</td><td>ON</td><td>ON</td><td>ON</td>

<td>40 ° C / 75% RH-open</td><td>ON</td><td>ON</td><td>ON</td><td>0</td><td>0.68</td><td>0.15</td><td>0</td><td>3.22</td><td>0.42</td><td>ON</td><td>ON</td><td>ON</td><td>ON</td><td>ON</td><td>ON</td><td>ON</td><td>ON</td><td>ON</td>

<td colspan="19">NA means "data not available"</td>

TABLE 2

Durability data for capsule formulations (DPP4 benzoate salt 4.8%, anhydrous lactose 50.2%, hydrated lactose 40%, croscarmellose sodium 2% and sodium stearyl fumarate 3%, the weight of bulking agents for 5 mg and 20 mg capsules are respectively 150 mg and 350 mg.)

<td rowspan="3">Conditions</td><td colspan="4">5 mg capsule</td><td colspan="4">20 mg capsule</td>

<td>2 weeks</td><td>⁴ weeks.</td><td>¹³ weeks.</td><td>26 weeks</td><td>2 weeks</td><td>⁴ weeks.</td><td>¹³ weeks.</td><td>26 weeks</td>

<td>Cis-CA%</td><td>Cis-CA%</td><td>Cis-CA%</td><td>Cis-CA%</td><td>Cis-CA%</td><td>Cis-CA%</td><td>Cis-CA%</td><td>Cis-CA%</td>

<td>25 ° C / 60% RH-closed</td><td>0.11</td><td>0.13</td><td>0.20</td><td>0.31</td><td>0.08</td><td>0.05</td><td>0.14</td><td>0.26</td>

<td>40 ° C / 75% RH-closed</td><td>0.23</td><td>0.35</td><td>0.61</td><td>0.95</td><td>0.22</td><td>0.26</td><td>0.46</td><td>0.62</td>

<td>50 C-closed</td><td>ON</td><td>0.73</td><td>1.72</td><td>ON</td><td>ON</td><td>0.43</td><td>1.19</td><td>ON</td>