OA17456A - Pharmaceutical compositions containing dexketoprofen and tramadol. - Google Patents

Pharmaceutical compositions containing dexketoprofen and tramadol. Download PDF

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OA17456A
OA17456A OA1201500313 OA17456A OA 17456 A OA17456 A OA 17456A OA 1201500313 OA1201500313 OA 1201500313 OA 17456 A OA17456 A OA 17456A
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international
pct
tramadol
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dexketoprofen
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OA1201500313
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Reinhard Schmitz
Tobias KOHL
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Laboratorios Menarini Sa
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Abstract

A pharmaceutical composition as a solid oral dosage form is described, comprising : i) a combination of two pharmacological active principles, dexketoprofen salt with an organic or inorganic base and tramadol salt with an organic or inorganic acid, wherein : the organic or inorganic base is selected in the group : trometamol, trimethylamine, dimethylamine, ethylamine, triethylamine, diethylamine, L-lysine, L-arginine, diethanolamine, sodium hydroxide, calcium hydroxide the organic or inorganic acid is selected in the group : hydrochloric, hydrobromic, phosphoric, sulfuric, methanesulfonic, benzenesulfonic, toluenesulfonic, acetic, propionic, malic, maleic, succinic, citric, L-tartaric, lactic, malonic, aspartic, glutamic; ii) microcrystalline cellulose as a filler; iii) a binder selected in the group : maize starch, pregelatinised maize starch, hypromellose or their mixtures; iv) pharmaceutically acceptable excipients.

Description

PHARMACEUTICAL COMPOSITIONS CONTAINING DEXKETOPROFEN AND TRAMADOL
FIELD OF THE INVENTION
The invention relates to a stable pharmaceutical formulation comprising the combination of the two active pharmaceutical ingrédients dexketoprofen and tramadol in a solid oral dosage form with immédiate release of both active ingrédients.
STATE OF THE ART
Dexketoprofen is the S-(+) enantiomer of the well known, non-steroidal antiinflammatory drug (NSAID) and réversible cyclooxygenase (COX) inhibitor, ketoprofen, with the chemical name S-(+)-2-(3-benzoylphenyl)propionic acid. Racemic ketoprofen is used as an analgésie and anti-inflammatory agent and these effects are due to the S-(+) enantiomer (dexketoprofen), while the R-(-) enantiomer does not contribute to these activities. The tromethamine sait of dexketoprofen is registered as 12.5 mg and 25 mg film-coated immédiate release oral tablets in EU countries and in several non-European countries for the symptomatic treatment of acute pain of mild to moderate intensity such as musculo-skeletal pain, dysmenorrhoea and dental pain.
Tramadol is the centrally acting opioid analgésie agent (lRS,2RS)-2[(Dimethylamino)methyl]-l-(3-methoxyphenyl)cyclohexanol. Tramadol is in the market since 1977 (Tramai®, Grünenthal). For oral use, tramadol is available as 50-300 mg capsules, tablets and sustained release formulations. Tramadol hydrochloride is the active ingrédient of products with marketing authorizations in many EU countries, such as Contramal® (ltaly), Adolonta® (Spain), Tramai® and Tramundin® (Germany). In addition, it is marketed in combination with other active ingrédients in préparations such as Zaldiar® contaîning 37.5 mg tramadol hydrochloride and 325 mg paracétamol.
The combination of analgésies has been the subject of numerous studies. The combination of a NSAID with an opioid was studied in the case of îbuprofen with oxycodon and ibuprofen with codeine. The combination of 400 mg îbuprofen and 5 mg oxycodon hydrochloride is marketed in the United States as Combunox®(Forest Pharmaceuticals, Inc.), As reported by Raffa et. al. in the US patent 5,516,803, the combination of tramadol and ibuprofen is synergistic for the treatment of pain and tussive conditions. The respective weight ratios were specîfied in the claims as 1:1 to 1:200 with the preferred ratios of about 1:2 to about 1:20.
In the publication by Tuncer et al. (Eur J Gynaecol Oncol. 2003;24(2): 181-4.), it was shown that clinically, ketoprofen seems to reduce morphine requirements by 33 to 40% with ketoprofen supposed central mechanism of analgesîa when administered intravenously. According to Siyam et al. in Anesthesiology 2003; 99: A996, the co-administration of tramadol and ketoprofen produced marked antinociceptive synergy and reduced side-effects
The rationale for developing an oral fixed combination of dexketoprofen and tramadol lies in the following considérations:
1. Dexketoprofen and tramadol hâve different mechanisms of action, the former exerts its anti-nociceptive activity maînly at peripheral level, whereas the latter is a centrally acting analgésie. Therefore their combination is expected to resuit in an additive or synergistic anaigesia, thus allowing a decrease in the required doses of the individual agents, and consequently a reduced risk of adverse events.
2. Dexketoprofen and tramadol hâve different pharmacokinetic profiles, therefore their combination is expected to be characterised both by quick onset (typical of dexketoprofen) and long duration (peculiar to tramadol) of the analgésie effect.
However in the literature there are a wealth of examples conceming technical hurdles in producing adéquate pharmaceutical préparations containing both ketoprofen and tramadol. For example, the common pharmaceutical excipient lactose monohydrate which is used in a variety of pharmaceutical compositions for oral use, e.g. tablets and film-coated tablets, leads to severe discoloration in tablets containing dexketoprofen, thus preventing its use.
Moreover, according to the literature, tramadol hydrochloride injection is found incompatible with acyclovir and clindamycin, while being stable when mixed with mannitol 20% or lactated Ringer’s solution. Furthermore, as assessed for tramadol 50mg/mL solution for injection or infusion, précipitation occurs when tramadol solution is mixed in the same syringe with solutions containing NSAIDs such as diclofenac sodium, îndometacin and piroxicam.
In EP546676 a pharmaceutical composition comprising tramadol and a propionîc acid dérivative NSAID, which may be ketoprofen, is described, the preferred composition consisting of tramadol with ibuprofen. The compositions described in the examples are aqueous solutions and consequently no particular problems with solid compositions were noted.
W02007008752 describes pharmaceutical compositions comprising two drugs which may be, among others, tramadol and a NSAID; the compositions are în a solid form, but the two drugs are in different layers for separate releases.
US6294195 discloses a sustained release oral analgésie dosage form for once-day administration comprising an opioid analgésie and optionally a non opioid drug. Tramadol and ketoprofen are included, but shown examples are referred just to morphine.
W02008/092219 discloses solid compositions with tramadol and ketoprofen. When mîxing the solid ketoprofen and tramadol, an interaction between the two active ingrédients is reported, as visualized by differentiai scanning calorimetry (DSC), resulting in a 'thick viscous mass hard to dissolve that could resuit in an alteration of the bioavailability of the drugs', The patent application further describes different options to 'vehicle tramadol and ketoprofen in pharmaceutical forms and / or products that prevent any contact between them and / or impede interaction between the two active principles’ assuming that the manufacturing following standard techniques and equipment is technically not feasible and will not lead to a stable pharmaceutical form. In this context, it should be noted that the intended field of treatment, namely moderate to severe pain, particularly demands the îmmediate-release of the active ingrédients which might be hindered by the physical interaction of ketoprofen and tramadol.
Additionally, as described by Botha et al. ( 1989) in Drug Development and Industrial Pharmacy 15 (3), 415-426, Botha et al. (1990) in Drug Development and Industrial Pharmacy 16 (4), 673-683, Tita et al (2011) in Journal of Pharmaceutical and Biomédical Analysis, 56, 221227, formulation development with ketoprofen and other NSAIDs such as naproxen is not trivial. Incompatibilities were detected for ketoprofen with common pharmaceutical filler materials such as lactose, calcium phosphates, magnésium stéarate or Precirol Ato 5 (glyceryl palmitostearate), which might resuit in increase of disintegration time, impaired dissolution rates and décomposition during stability storage.
In addition, in AU703310B2 (EP7592963) Ά rapidly disintegrating médicinal form of tramadol or a tramadol sait', the préparation of binder-free tablets containing tramadol is described, since the development of binder-containing tablets with tramadol that show fast disintegration and dissolution is considered as not possible. In detail, it was outlined that tramadol hydrochloride closes the capillaries of a tablet during disintegration due to the high water solubility of this compound and leads to the rapid formation of a highly concentrated diffusion boundary layer. Moreover, the disintegration cannot be accelerated by increasing the content of disintegrating agent.
The unfavourable characteristics of tramadol in terms of drug product development become even more pronounced when it îs combined with dexketoprofen. In fact, due to its sticky nature and the tendency to agglomerate, the latter should require the further processing in the form of binder-containing granules so precluding any binder-free tablets.
DESCRIPTION OF THE INVENTION
The drawbacks associated with the technology described in W02008/092219 are overcome by the présent invention, which provides the appropriate methodology to préparé pharmaceutically acceptable solid oral formulations of dexketoprofen and tramadol, both as salts,
on the basis of standard techniques and equipment without the need of specialized procedures.
From the technological point of view, the basic principles for the manufacturing of these formulations, without the complex methodology which requires the séparation of both active ingrédients from each other, were identified and consist in:
The active principles are both used as salts.
The use of an appropriate filler material.
- The use of an appropriate binder system for the granulation, inducing a suitable granule size and granule structure.
- The use of an appropriate technology for the manufacturing, particularly in the case of the granulation procedures, i.e. by fluid bed granulation leading to a soft and easily disintegrating /dissolving granule structure which is especially suitable for a solid, immediaterelease dosage form.
In order to avoid the potential physical incompatibility of dexketoprofen and tramadol and the formation of a hard and sticky mass as outlined in W02008/092219, it is necessary to follow the established principles as described above and in the examples illustrated below. The combination of the identified parameters induces a stable and technologically feasible pharmaceutical dosage form suitable for the treatment of acute pain of moderate to severe intensity originated by different causes and related to different diseases such as; post-operative pain, headache, toothache, backpain, joint pain, inflammations and migraine.
According to W02008/092219 the technological formulation of dexketoprofen and tramadol should necessitate the use of specialised, intricate techniques such as multi-layered tabletting, separate granulation of both active ingrédients and / or the packaging in separate blister moldings in order to keep the two active ingrédients rigorously separated. Surprisingly, however, the présent invention shows that the manufacturing of a pharmaceutically stable formulation of these two active ingrédients, suitable for the treatment of moderate to severe pain, is feasible without the application of non-standard methods and technologies. The présent invention provides a technologically stable formulation containing the active principles dexketoprofen and tramadol together with excipients in pharmaceutically acceptable quality, in particular fillers and bînders, wherein the filler is microcrystalline cellulose and the binder is preferably selected in the group of maize starch, pregelatinised maize starch, hypromellose or their mixtures.
For the purposes of the présent invention hypromellose indicates hydroxypropylmethylcellulose or HPMC.
In a preferred embodiment, dexketoprofen is used as tromethamine (trometamol) sait and
tramadol as the hydrochloride sait. Moreover, the production of the pharmaceutical dosage forms is performed with standard galenical processes such as mixing, sieving, granulating, tabletting and film-coating while applying standard technological equipment and machinery. Therefore, both active ingrédients are not separated by specîalized or unique manufacturing and or / packaging procedures such as tabletting in multi-layers, tabletting of two different granules / film-coated crystals or packaging in blisters with separated moldings.
According to the invention, dexketoprofen is in the form of a sait with organic or inorganic bases and tramadol as a sait with organic or inorganic acids.
The organic or inorganic base is selected from the group of trometamol, trimethylamine, dimethylamine, ethylamine, triethyl amine, diethylamine, L-lysine, L-arginine, diethanolamine, sodium hydroxide, calcium hydroxide; the preferred being trometamol.
For the purposes of the présent invention trometamol indicates 2-amino-2hydroxymethyl-l,3-propanediol, also known as tromethamine or TRIS.
The organic or inorganic acid is selected from the group of hydrochloric, hydrobromic, phosphoric, sulfuric, methanesulfonic, benzenesulfonîc, toluenesulfonic, acetic, propionic, malic, maleîc, succinic, citric, L-tartaric, lactic, malonic, aspartic, glutamic; the preferred being hydrochloric.
The combination is directed to the treatment of acute and postoperative pain of moderate to severe intensity originated by different causes and related to different diseases selected from the group of headache, toothache, inflammations and migraine. The fixed combination of both compounds is intended to allow optimised pain control with fewer side effects than observed for both compounds alone.
According to the présent invention the pharmaceutical forms comprise solid oral dosage forms, preferably immedîate-release film-coated tablets.
According to the présent invention, the pharmaceutical compositions contaîn a mixture of the two active ingrédients, for oral dosage unit, in the following amount:
- Dexketoprofen (mol wt 254.28): between 8 and 50 mg, preferably between 10 and 30 mg, 12.5 mg and 25 mg being the most preferred amounts (équivalent to dexketoprofen trometamol (mol wt 375.42) between 11.8 and 73.8 mg, preferably between 14.8 and 44.3 mg, 18.4 mg and 36.9 mg being the most preferred spécifie amounts).
- Tramadol (mol wt 263.28): between 17.6 and 105.4 mg, preferably between 26.3 and
87.8 mg, 32.9 mg and 65.9 mg being the most preferred spécifie amounts [équivalent to tramadol hydrochloride (mol wt 299.84) between 20 and 120 mg, preferably between 30 and 100 mg, 37.5 mg and 75 mg being the most preferred amounts].
The pharmaceutical compositions contain a mixture of the two active ingrédients for oral dosage unit in a w/w ratio of dexketoprofen / tramadol between 2: 1 to 1: 10, preferably in a w/w ratio between 1: 1 to 1: 6 (équivalent to a w/w ratio of dexketoprofen trometamol / tramadol hydrochloride between 2.59:1 to 1: 7.7, preferably 1.3: 1 to 1: 4.63).
The pharmaceutical compositions may contain in addition to the active ingrédients one or more pharmaceutically acceptable excipients selected from pharmaceutical fillers, binders, disintegrants, lubricants and glidants.
The filler consists of microcrystalline cellulose and it should be contained in each dosage unit from 45% to 75% w/w of the total amount.
The binder, selected in the group consisting of maîze starch, pregelatinised maize starch, hypromellose or mixtures thereof, in amounts from 5% to 20%, preferably from 7% to 12% by the total weight of the composition.
The disintegrant is selected from croscarmellose sodium and sodium starch glycolate or mixtures thereof, in amounts from 4% to 14% by the total composition weight.
The lubricant is selected în the group consisting of glycerol di stéarate, sodium stearyl fumarate or mixture thereof, sodium stearyl fumarate being the preferred one.
The preferred glidant is anhydrous colloïdal silica.
According to the présent invention, ail the components of the compositions are intimately mixed. With the term intimately mixed a mixing of the components, and in particular of the two active principles, is intended in such a way that a physical contact among the components of the compositions, and in particular between the two active principles, is never precluded.
Oral dosage unit may optionally be coated with pharmaceutical excipients selected from pharmaceutical film formers, pigments, dispersants and polishing agents.
Dosage units are preferably coated with hypromellose or a poly(vinyl) alcohol based outer film coating.
Not ail standard pharmaceutical excipients can be used together with dexketoprofen and tramadol. The use of lactose monohydrate which is a standard pharmaceutical excipient commonly used as filler material in combination with microcrystalline cellulose (e.g. MicroceLac®) is not possible with dexketoprofen. The resulting tablets show yellow to orange stains indicating a chemical incompatibility and a significantly increased disintegration time after accelerated stability testing.
Also the use of the common binder polyvînylpyrrolidone (PVD) is precluded, as it leads to dull, porous tablet cores which are not suitable for further processing such as film coating, and to a strong increase in disintegration time and résistance to crushing.
Surprisîngly pharmaceutical compositions containing i) a sait of dexketoprofen, trometamol being the preferred, ii) a sait of tramadol, hydrochloride being the preferred, iii) microcrystalline cellulose, as a filler, in high percentage w/w of the total amount, iv) a binder, v) one or more pharmaceutically acceptable excipients, wherein ail the constituents are intimately mixed, resuit to be stable in ail the studied conditions.
The pharmaceutical compositions can be manufactured following standard galenical processes in which both ingrédients are not separated by specialized or unique manufacturing and ! or packaging procedures; they can be manufactured by fluid bed granulation or fluid bed drying in tablets or capsules for the immediate-release of both active principles.
The compositions prepared according to the présent invention show a dissolution of the two active Ingrédients, dexketoprofen and tramadol, in a time range not superior to 15 minutes, more precîsely between 3 and 11 minutes.
The compositions show a dissolution rate and a purity profile of the components which remain un-changed during shelf-life of 18 months at (25 ± 2)°C and (60 ± 5)% relative humidity in aluminium-aluminium and PVC/PVDC-aluminium blisters.
EXPERIMENTAL SECTION
Dexketoprofen shows a pronounced physicochemical incompatibility with tramadol. This interaction is elucidated below (Example A).
Example A: Compatibility testing of dexketoprofen trometamol and tramadol hydrochloride as dry powder mixtures
Dexketoprofen trometamol and tramadol hydrochloride were mixed together at different ratios and subjected to accelerated conditions, i.e. (60 +/- 2)°C and 60% relative humidity. The corresponding results are presented in table A1.
Table A - Appearance of dry powder mixtures containing dexketoprofen and tramadol
Composition Results (after weeks)
0 1 2 4
Dexketoprofen trometamol (DKP TRIS) n.t. n.t. loose powder agglomerated powder
Tramadol hydrochloride (TRA-HC1) n.t. n.t. loose powder slightly agglutinated powder
DKP TRIS + TRA-HC1 (25 mg + 37,5 mg) n.t. loose powder n.t. agglomerated powder
DKP TRIS + TRA-HC1 (12.5 mg+ 75 mg) n.t. hard and agglutinated mass at the bottom of the vial n.t. hard and agglutinated mass at the bottom of the vial
n.t. = not tested
These results demonstrate the physical interaction between dexketoprofen trometamol and tramadol hydrochlorîde drug substances, especially in the case of high tramadol doses (e.g. 75 or 100 mg).
The resuit obtained in EXAMPLE A makes it unlikely for the person skilled in the art to define an effective and stable pharmaceutical composition of both components in the form of a binder-containing tablet. As shown in the following EXAMPLES l to 4 of the présent invention, however, the sélection of the right components applied in the correct ratio and processed in the appropriate manufacturing procedures décidé about the functionality and stability of drug 10 product. The comparative EXAMPLES B and C are provided to illustrate this fmding.
EXAMPLE B: Sélection of the appropriate bînder System for dexketoprofen + tramadol tablets
For the définition of the appropriate binder System of dexketoprofen + tramadol drug product, conventional pharmaceutical binders such as polyvinylpyrrolidone, hypromellose and 15 pregelatinized maize starch were evaluated.
The tablets were manufactured in accordance with the composition presented in table B.
Table B - Composition of tablet cores used for the screening of the appropriate bînder system
1 36.90 1 (25.0) '75.00 | 309.30 1 1 14.04 18.72 Ό en o< 4.68 q.s. 468.00
o
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en en r- CM 1 1 CM et σ’ et
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3
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to un r*q O un \d r- 00 te r- 00 .36 .68 cZ 00 te
Q. CM en r- CM 1 xr 1 Ot Tt- CF1 'T
WD S
r» *
c o Q] o O 'T CM 00
CS 5 o Ch to uS rq O un σ< rn CM Γ- ΟΟ .36 .68 cZ 00 te
t—1 en t- CM 00 1 1 Ot ’Φ CT1 t
C
O
» t-M
rt
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•n Ό à
O o
&) Ëb « Um Λ
fi o c Q C o h h Um w C rt o c M—> fi
U s 3 > Q > -i-J Q Ui JD Ό _C T3 £ T3 c 'cft •C x> 3 rt TJ OJ o
fe < < IX S m ffl Q U o en
w
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u H _o *4—>
c ,rt «J ω U U Um* Um Um Um Um* U Um
te G G 3 3 3 G 3 3 G
n c ’o m w W W W W W W m
« u O- x 33 Æ 33 33 3 33 33 33
K <Λ B- X Cl, PL, Cl. PL, û. PL, Cl,
__!
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i Q
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g P N G
O fc Um tx o w ω T3 'C o 3 Q um £ T5 -C _go '3
f U <u Ό O 'S £ ne cel c o 3 S 00 £ G, o C/l ω O M-J rt ü3 -G C M * £ ω Îq Q
Ingrédient Dexketoprofei (équivalent to Tramadol hyd Microcrystallî Polyvinylpyrri Maize starch, Hypromellose Croscarmellos Glycerol diste Silica colloida Purified water Total tablet c
ω c o
S l c
ίΰ ,g = bînder system pregelatinîzed maize starch, = bînder system hypromellose 5% w/w = bînder system hypromellose 3% w/w
CM
-sfr un
ίο
The amount of polyvinylpyrrolîdone was selected in accordance with previous expériences leading to a favourable particle size and granule properties. Ail the mixtures were sieved, granulated and subjected to tablet compaction. The appearance of the resulting tablet cores is presented in table C.
Table C - Appearance of tablet cores manufactured with different bînder Systems
Parameter Formulation
1 2 3 4
Appearance of the tablet cores dull, slightly porous shiny, brilliant dull, dark- spotted slightly shilling
n.t. = not tested
Subsequently, the tablet cores were subjected to accelerated stability testing at 60°C and tested for disîntegration time and tablet hardness (tables E and F).
Table D - Disîntegration time of dexketoprofen + tramadol formulations in tablets with different bînder Systems
Formulation Disîntegration time [mîn.] after weeks at 60°C
0 2 4
1 (polyvinylpyrrolîdone) 3 16 17
2 (maize starch pregelatinîzed) 2 7 10
3 (hypromellose 5% w/w) 3 8 8
4 (hypromellose 3% w/w) 2 6 4
Table E - Résistance to crushing of dexketoprofen + tramadol formulations in tablets with different binder Systems
Formulation Résistance to crushing [N] after weeks at 60°C
0 2 4
1 (polyvinylpyrrolidone) 90 123 123
2 (maize starch pregelatinized) 134 127 116
3 (hypromellose 5% w/w) 128 120 119
4 (hypromellose 3% w/w) 165 126 122
The obtained results from binder screening underline that the number of suitable binders for dexketoprofen + tramadol containing tablets îs limited. The use of the standard binder polyvinylpyrrolidone is precluded, as it leads to dull, porous tablet cores which are not suitable for further processing such as film coating, and to a strong increase of disintegration time and résistance to crushing. The increase of disintegration time was also detected for tablet cores formulated on the basis of pregelatinized maize starch and hypromellose 3% w/w and 5% w/w, but to a far lesser extent and without the increase of tablet hardness. Therefore, any binder system containing the commonly used polyvinylpyrrolidone does not allevîate the incompatibility of dexketoprofen and tramadol, but rather seems to support the négative effects of this interaction. After storage at accelerated conditions, the obtained tablet cores are no longer compilant with the requirements of Ph. Eur., i.e. disintegration time below 15 minutes.
EXAMPLE C illustrâtes the possible option to overcome the observed increase în disintegration time in tablet cores with maize starch, pregelatinized, by the application of an appropriate lubricant system.
EXAMPLE C: Sélection of the appropriate lubricant in combination with appropriate binder system
In order to dimînish the observed increase in disintegration time over shelf-life, different types of lubricant were tested in tablet cores formulated with maîze starch pregelatînized. As magnésium stéarate was described in literature to be incompatible with (dex)ketoprofen (2) and naproxen (3), this excipient was excluded, so that the study was conducted with glycerol distearate and sodium stearyl fumarate. The corresponding formulations and results are 5 summarized in tables F and G.
Table F - Composition of tablet cores used for the lubricant screening
Ingrédient Reference Function Quantity, mg per tablet
1 2
Dexketoprofen trometamol (équivalent to dexketoprofen) Manufacturer spécification Active ingrédient 36.90 (25.0) 36.90 (25.0)
Tramadol hydrochloride Ph. Eur. Active ingrédient 75.00 75.00
Microcrystalline cellulose Ph. Eur. Filler 253.14 253.14
Maize starch, pregelatînized Ph. Eur. Binder 46.80 46.80
Croscarmellose sodium Ph. Eur. Disintegrant 46.80 18.72
Glycerol distearate Ph. Eur. Lubricant 4.68 -
Sodium stearyl fumarate Ph. Eur. Lubricant 4.68
Silica colloïdal, anhydrous Ph. Eur. Glidant 4,68 4.68
Purified water* Ph. Eur. Solvent for granulation q.S. q.S.
Total tablet core weight 468.00 468.00
Table G - Disintegration time of dexketoprofen + tramadol formulations in tablets with different types of lubricant
Formulation Disintegration time [min.] after weeks at 60°C
0 1 4
1 (glycerol distearate) 2 4 5
2 (sodium stearyl fumarate) 3 2 3
The disintegration time of tablet cores prepared with 1% w/w glycerol distearate significantly increased from 2 min. to 4 min. after 1 week and to 5 min. after 4 weeks at 60°C. In contrast, tablet cores with identical parameters and identical formulation except for the use of 1% sodium stearyl fumarate instead of glycerol distearate showed no increase at ail in the disintegration time (3 min. at point zéro vs. 2 min. after 1 week and vs. 3 min after 4 weeks at 60°C).
In summary, the experimental EXAMPLES A to C indicate that the formulation development for dexketoprofen + tramadol tablets requires spécifie strategies and that the number of potential excipients that are appropriate is limited.
BRIEF DESCRIPTION OF THE DRAWNINGS
Figure 1, 2 and 3 are graphs showing the dissolution behaviour of both active ingrédients, dexketoprofen TRIS and tramadol hydrochloride, respectively at the initial conditions and after accelerated stability tests (1 and 4 weeks at 60°C). The dissolution tests were performed, according to USP, in pH 6.8 RI buffer, using a paddle apparatus, at a speed of 50 rpm and in a volume of 1000 ml.
Figure 4: shows the dissolution profile of the film-coated tablets of dexketoprofen TRIS and tramadol hydrochloride derived from a pilot batch production, at the initial conditions.
Figure 5: shows the dissolution profile of the film-coated tablets of dexketoprofen trometamol and tramadol hydrochloride originated from the first manufactured sub-batch of 1 OOKg at the initial conditions.
Figure 1 : Dissolution profile of active ingrédients, initial conditions.
Figure 2: Dissolution profile of active ingrédients after 1 week at 60°C.
Figure 3: Dissolution profile of active ingrédients after 4 weeks at 60°C.
Figure 4: Dissolution profile of film-coated tablets (pilot batch), initial conditions.
Figure 5: Dissolution profile of film-coated tablets (100 kg manufactured sub-batch), initial conditions.
EXAMPLES
The examples comprise solid oral dosage forms in several combinations. However, the 5 dosage strengths which can be prepared with the présent invention are not limited to these combinations only.
The detailed description of the examples is intended to illustrate the invention, but not to limit its scope.
EXAMPLE 1: Manufacturing of dexketoprofen trometamol + tramadol hydrochloride 10 tablet or film-coated tablets, with maîze starch
Batch size: 4 kg
The composition and batch formulas of the (film-coated) tablets with the combination dosage strengths DKP TRIS 18.4 mg + TRA-HC1 37.5 mg (1), DKP TRIS 18.4 mg + TRA-HC1 75 mg (2), DKP TRIS 36.9 mg + TRA-HC1 37.5 mg (3) and DKP TRIS 36.9 mg + TRA-HC1 75 15 mg (4) are given in table 1 and table 2, respectively.
Table 1 - Composition of the tablets and film-coated tablets, respectively:
Ingrédient Reference Function Quantity, mg per tablet
1 2 3 4
Tablet core
Dexketoprofen trometamol (équivalent to dexketoprofen) Manufacturers spécification Active ingrédient 18.45 (12.5) 18.45 (12.5) 36.90 (25.0) 36.90 (25.0)
Tramadol hydrochloride Ph. Eur. Active ingrédient 37.50 75.00 37.50 75.00
Microcrystalline cellulose Ph. Eur. Filler 378.85 341.35 360.40 322.90
Maize starch Ph. Eur. Binder 49.60 49.60 49.60 49.60
Ingrédient Reference Function Quantity, mg per tablet
1 2 3 4
Sodium starch glycolate Ph. Eur. Disintegrant 27.10 27.10 27.10 27.10
Glycerol distearate Ph. Eur. Lubricant 5.20 5.20 5.20 5.20
Silica colloïdal, anhydrous Ph. Eur. Glidant 3.30 3.30 3.30 3.30
Purified water* Ph. Eur. Solvent for granulation q.s. q.s. q.s. q.s.
Total tablet core weight 520.00 520.00 520.00 520.00
Film-coating (optional)
Hypromellose Ph. Eur. Film former 4.95 4.95 4.95 4.95
Titanium dioxide Ph. Eut. Pigment 3.24 3.24 3.24 3.24
Povidone K 30 Ph. Eur. Dispersant 0.87 0.87 0.87 0.87
Macrogol 4000 Ph. Eur. Polishing agent 0.95 0.95 0.95 0.95
Purified water* Ph. Eur. Solvent for film-coating q.s. q.s. q.s. q.s.
Total weight of film coated tablet 530.01 530.01 530.01 530.01
* not part of the final drug product
Table 2 - Batch formulas of the tablets and film-coated tablets, respectively:
Ingrédient Reference Quantity, g per batch
1 2 3 4
Ingrédient Reference Quantity, g per batch
1 2 3 4
Tablet core
Dexketoprofen trometamol Manufacturers spécification 141.923 141.923 283.846 283.846
Tramadol hydrochloride Ph. Eur. 288.462 576.923 288.462 576.923
Microcrystalline cellulose Ph. Eur. 2914.231 2625.769 2772.308 2483.846
Maize starch Ph. Eur. 381.538 381.538 381.538 381.538
Sodium starch glycolate Ph. Eur. 208.462 208.462 208.462 208.462
Glycerol distearate Ph. Eur. 40.000 40.000 40.000 40.000
Silica colloïdal, anhydrous Ph. Eur. 25.385 25.385 25.385 25.385
Purified water (solvent for granulation) * Ph. Eur. q.S. q.s. q.s. q.s.
Film coating (optional)
Hypromellose Ph. Eur. 38.077 38.077 38.077 38.077
Titanium dioxide Ph. Eur. 24.923 24.923 24.923 24.923
Povidone K 30 Ph. Eur. 6.692 6.692 6.692 6.692
Macrogol 4000 Ph. Eur. 7.308 7.308 7.308 7.308
Purified water Ph. Eur. q.s. q.s. q.s. q.s.
Ingrédient Reference Quantity, g per batch
1 2 3 4
(solvent for film coating)*
Dexketoprofen trometamol anc tramadol bydrochlorîc e are sieved together
iïiicrocrystalline cellulose and about ‘A of maize starch through 1.0 mm mesh size. The compounds are mixed for 20 min. With the remaining amount of maize starch the granulation fluid is prepared: approximately 1/3 of water is mixed with the second half of maize starch. The remaining water is heated to near the boiling point and then added to the maize starch slurry. For the wet granulation the binder fluid is stirred to 72-80°C. The granulation is performed applying standard procedures using a fluid bed granulator. It is dried to a loss on drying of 2.5 - 3.5%. Afterwards, the granules are sieved (1.0 mm mesh size) and subsequently mixed with sodium starch glycolate, glycerol distearate and silica colloïdal anhydrous for 10 min. The obtained compactable mixture is compressed on a standard rotary die press to tablet cores with the following properties:
- Oblong with dimensions of 17x8 mm
- Tablet mass: 520 ± 3%
- Height: 5.5 ± 0.2 mm
- Résistance to crushing: > 90 N
- Disintegration time: < 5 min.
- Friability: < 1.0%
The resulting tablet cores can be coated with the hypromellose film. The hypromellose is added to purified water heated to near the boiling point. Afterwards, povidone K 30 and macrogol 4000 are added and the mixture is stirred until a clear solution is obtained. Directly before the film-coating, titanium dioxide is added and dispersed with a high frequency stirrer. The film-coating is performed in a standard film-coater.
The obtained film-coated tablets show the following properties:
- Tablet mass: 530 ± 5%
- Height: 5.6 ± 0.3 mm
- Résistance to crushing: > 90 N
- Disintegration time: < 7.5 min.
Sample batches with different dexketoprofen/tramadol ratios were produced and tested under ICH conditions for 18 months at (25 ± 2)°C and (60 ± 5)% relative humidity. Results of
these tests are presented in tables 3 to 6.
The obtained results indicate excellent chemical and physical stability of the produced batches (regarding disintegration, dissolution and other tablet parameters).
Table 3 - Stability data of the film-coated tablets DKP TRIS 18.4 mg + TRA-HC1
37.5mg at (25 ± 2)°C and (60 ± 5)% RH in Al-Al blisters:
Test parameters Shelf-life Results (after months)
spécification 0 3 6 9 12 18
General and spécifie characteristics of the dosage form
Dissolution (after 30 min)
Dexketoprofen TRIS [%] (Q=75) 101 98 99 100 101 101
Tramadol hydrochloride [%] (0=75) 102 102 101 102 102 102
Disintegration time [min] nmt 15 3 4 5 4 3 4
Assay
Dexketoprofen TRIS [%] 90.0 to 105.0 99.4 102.1 100.2 100.7 100.4 102.2
Tramadol hydrochloride [%] 90.0 to 105.0 99.7 101.8 102.9 102.0 101.6 105.0
Additional parameter
Z
Résistance crushing to
- mean t:>90N 203 252 198 189 189 199
nmt = not more than
Table 4 - Stability data of the film-coated tablets DKP TRIS 18.4 mg + TRA-HC1 75mg at (25 ± 2)°C and (60 ± 5)% RH in Al-Al blisters:
Test parameters Shclf-lifc spécification Results (after months)
0 3 6 9 12 18
General and spécifie characteristics of the dosage form
Dissolution (after 30 min)
Dexketoprofen TRIS[%] (0=75) 102 100 101 101 98 102
Tramadol hydrochioride [%] (Q=75) 103 100 102 100 100 102
Disîntegration time [min] nmt 15 6 7 9 9 11 8
Assay
Dexketoprofen TRIS [%] 90.0 to 105.0 99.1 101.7 101.3 103.3 100.9 101.6
Tramadol hydrochloride [%] 90.0 to 105.0 99.2 101.8 101.3 103.1 101.1 101.2
Additional parameter
Résistance to crushing
- mean t: > 90 N 200 224 189 194 183 192
nmt = not more than
Table 5 - Stability data of the film-coated tablets DKP TRIS 36.9 mg + TRA-HCl
37.5mg at (25 ± 2)°C and (60 ± 5)% RH in Al-Al blisters:
Test parameters Shelf-life spécification Results (after months)
0 3 6 9 12 18
General and spécifie characteristics of the dosage form
Dissolution (after 30 min)
- Dexketoprofen TRIS [%] (0=75) 102 101 102 100 101 102
Tramadol hydrochloride [%] (0=75) 101 100 100 100 100 101
Disintcgration time [min] nmt 15 3 5 6 3 1 3
Assay
Dexketoprofen TRIS [%] 90.0 to 105.0 98.2 102.3 101.6 102.2 101.1 102.4
Tramadol hydrochloride [%] 90.0 to 105.0 96.8 100.5 101.4 100.8 98.7 101.4
Additional parameter
Résistance to crushing
- mean t: > 90 N 207 257 190 205 203 204
nmt = not more than
Table 6 - Stability data of the film-coated tablets DKP TRIS 36.9 mg + TRA-HC1 75mg at (25 ± 2)°C and (60 ± 5)% RH in Al-Al blisters:
Test parameters Shelf-life spécification Results (after months)
0 3 6 9 12 18
General and spécifie characteristics of the dosage form
Dissolution (after 30 min)
- Dexketoprofen TRIS [%] (0=75) 104 103 103 n. t. 101 99
Tramadol hydrochloride [%] (Q=75)(1) 104 101 102 n. t. 103 99
Disintegration time [min] nmt 15 3 8 9 8 7 8
Assay
Dexketoprofen TRIS [%] 90.0 to 105.0 100.5 103.1 103.0 103.2 104.9 104.1
Tramadol hydrochloride [%] 90.0 to 105.0 100.6 102.4 103.1 103.4 102.7 102.6
Additional parameter
Résistance to crushing
- mean t: > 90 N 152 184 170 167 174 183
nmt = not more than
EXAMPLE 2: Manufacturing of dexketoprofen trometamol + tramadol hydrochloride film-coated tablets with pregelatinised maize starch
Batch size: 550g
Composition of the film-coated tablets:
Active substances Amount per single dose unit [mg] Amount per batch [g]
Dexketoprofen trometamol 36.90 57.99
Tramadol hydrochloride 75.00 117.86
Other ingrédients
Tablet core:
Microcrystalline cellulose 179.70 282.39
Maize starch pregelatinised 29.20 45.89
Croscarmellose sodium 21.90 34.41
Sodium stearyl i uni ara te 3.65 5.74
Silica, colloïdal anhydrous 3.65 5.74
Purified water* q.s. q.s.
Film coating:
polyvinyl alcohol based coating 7.30 11.47
Purified water* q.s. q.s.
* not part of the final product
Dexketoprofen trometamol and tramadol hydrochloride are sieved together with microcrystalline cellulose and ’Λ of croscarmellose sodium through 1.0 mm mesh size. The compounds are transferred to the fluid bed granulator. For the préparation of the binder fluid pregelatinised maize starch is added to purified water and stirred for about 60 min. in order to obtain homogenous binder slurry. The granulation is performed applying standard procedures in a fluid bed granulator. It is dried to a loss on drying of 2.5 - 3.5%. Afterwards, the granules are sieved (1.0 mm mesh size) and subsequently mixed with croscarmellose-sodium, silica, colloïdal anhydrous for 10 min. After the mixture with sodium stearyl fumarate for 5 min., the obtained compactable mixture is compressed on a standard rotary tablet press to tablet cores with the following properties:
- Oblong with dimensions of 16x7 mm
- Tablet mass: 350 mg ± 5%
- Height: 4.5 ± 0.2 mm
- Résistance to crushing: > 90 N
- Disintegration time: < 4 min.
- Friability: < 1.0%
The resulting tablet cores are subsequently coated with an aqueous film coating System based on a polyvinyl alcohol motif, which is prepared according to the manufacturer’s recommendation. The film-coating is performed in a standard fihn-coater. The resulting filmcoated tablets show the following properties:
- Tablet mass: 357 mg ± 5%
- Height: 4.6 ± 0.2 mm
- Résistance to crushing: > 90 N
- Disintegration time: < 6 min.
The dissolution profiles of the film-coated tablets in Ph. Eur. buffer pH 6.8 RI with paddle apparatus, at 50 rpm of stirring speed and 1000 ml of buffer volume are shown in figures 1, 2 and 3. Figure 1 présents the dissolution profiles of both active ingrédients at the initial value, whereas figures 2 and 3 displays the dissolution profiles after accelerated stability testing for 1 and 4 weeks, respectively, at 60°C in a dry oven. No significant différence between the dissolution profiles was détectable, so that a physïco-chemical interaction of both compounds
can be excluded.
EXAMPLE 3: Manufacturing of dexketoprofen + tramadol film-coated tablets with pregelatinised maize starch as binder and croscarmellose sodium as disintegrant in pilot batch scale (12.7 kg)
The identical formulation as presented in EXAMPLE 2 was upscaled to 12.7 kg (pilot scale). The characteristics for the tablet cores are presented below:
- Oblong with dimensions of 14x6 mm
- Tablet mass: 350 mg ± 5%
- Height: 5.1 ± 0.5 mm
- Résistance to crushing: 130 ± 15 N
- Disintegration time: < 6 min.
- Friability: < 0.5%
The properties of the film-coated tablets are as follows:
- Tablet mass: 357 mg ± 5%
- Height: 5.2 ± 0.5 mm
- Résistance to crushing: > 90 N
- Disintegration time: < 15 min.
The film-coated tablets were tested for the dissolution profile and for stability under accelerated conditions at 40°C ! 75% relative humidity. The results are presented in figure 4 and table 7.
Table 7 - Stability data of the film-coated tablets DKP TRIS 36.9 mg + TRA-HC1 75mg at (25 ± 2)°C and (60 ± 5)% RH in Al-Al blisters
Test parameters Shelf-life spécification Results (after months)
0 3 6
General and spécifie characteristics of the dosage form
Dissolution (after 30 min)
- Dexketoprofen TRIS [%] (Q=75)(l) 98 101 98
Tramadol hydrochloride [%] (Q=75) (l) 99 102 99
Disintegration time [min] nmt 15 6 7 6
Assay
Dexketoprofen TRIS [%] 90.0 to 105.0 101.3 99.6 99.2
Tramadol hydrochloride [%] 90.0 to 105.0 102.7 101.4 100.8
Additional parameter
Résistance to crushing [N](7) t:>90 191 228 233
EXAMPLE 4: Manufacturing of dexketoprofen + tramadol film-coated tablets with pregelatinised maize starch as binder and croscarmellose sodium as disintegrant in the large scale of223 kg
The formulation from EXAMPLES 2 and 3 was slightly modified and upscaled to the large-scale batch size of 223 kg. The granulation was performed in two sub-batches.
Composition of the film-coated tablets:
Active substances Amount per single dose unit [mg] Amount per granulation sub-batch [kg] Amount per batch [kg]
Dexketoprofen trometamol 36.90 11.121 22.241
Tramadol hydrochloride 75.00 22.603 45.206
Other ingrédients
Tablet core:
Microcrystalline cellulose 179.70 54.157 108.314
Maize starch pregelatinised 29.20 8.800 17.600
Croscarmellose sodium (inner phase) 11.02 3.321 6.642
Croscarmellose snrlium /miter ntiasel 22.04 - 13.292
Sodium stearyl fiimarate 1.83 - 4.442
Silica, colloïdal anhydrous 7.37 - 1.103
Purified water* q.s. -
Film coating:
polyvinyl alcohol based coating 7.30 - 4.400
Purified water* q.s. - q.s.
For the first sub-batch of 100 kg, dexketoprofen trometamol, tramadol hydrochloride, microcrystalline cellulose and croscarmellose-sodium for the inner phase mixed and sieved together through 1.0 mm mesh size. The compounds are transferred to the fluid bed granulator. For the préparation of the binder fluid pregelatinised maize starch is added to purified water and 5 stirred for about 60 min. in order to obtain a homogenous binder slurry. The granulation is performed applying standard procedures in a fluid bed granulator. It is dried to a loss on drying of 2.5 - 3.5%. Afterwards, the granules are sieved (1.0 mm mesh size) and subsequently mixed with croscarmellose-sodium and silica, colloïdal anhydrous for 10 min. The second sub-batch is prepared following identical procedures and then added to the first sub-batch. Sodium stearyl 10 fiimarate is sieved and added to the mixture of both sub-batches. The obtaîned compactable mixture is compressed on a standard rotary tablet press to tablet cores with the following properties:
L·
- Oblong with dimensions of 14x6 mm
- Tablet mass: 363 mg ± 2%
- Height: 5.1 ±0.2 mm
- Résistance to crushing: 115 -150 N
- Disintegration time: < 5 min.
- Friability: < 0.05%
The properties of the film-coated tablets are as follows:
- Tablet mass: 370 mg ± 5%
- Height: 5.2 ± 0.2 mm
- Résistance to crushing: > 90 N
- Disintegration time: < 6 min.
Table 8 - Stability data of the film-coated tablets DKP TRIS 36.9 mg ± TRA-HC1 75mg at (40 ± 2)°C and (75 ± 5)% RH in Al-Al blisters
Test parameters Shelf-life spécification Results (after months)
0 3 6
General and spécifie characteristics of the dosage form
Dissolution (after 30 min)
- Dexketoprofen TRIS [%] (0=75) 100 98 98
Tramadol hydrochloride [%] (0=75) 100 98 100
Disintegration time [min] nmt 15 8 8 9
Assay
Dexketoprofen TRIS [%] 90.0 to 105.0 98.7 99.5 98.8
Tramadol hydrochloride [%] 90.0 to 105.0 100.5 100.1 100.0
Additional parameter
Résistance to crushing [N] t:>90 221 255 266
Table 9 - Stability data of the film-coated tablets DKP TRIS 36.9 mg + TRA-HCl 75 mg at (30 ± 2)°C and (75 ± 5)% RH in Al-Al blisters
Test parameters Shelf-life spécification Results (after months)
0 3 6
General and spécifie characteristics of the dosage form
Dissolution (after 30 min)
- Dexketoprofen TRIS [%] (Q=75) 100 94 96
Tramadol hydrochloride [%] (Q=75) 100 95 95
Dîsintegration time [min] nmt 15 8 8 8
Assay
L·
Dexketoprofen TRIS [%] 90.0 to 105.0 98.7 100.1 97.6
Tramadol hydrochloride [%] 90.0 to 105.0 100.5 100.8 99.9
Additional parameter
Résistance to crushing [N](7) t: > 90 221 232 245
The dissolution profile of the obtained film-coated tablets is shown in figure 5 and is comparable to that of the sample and pilot size batches.
1. A pharmaceutical composition in a solid oral dosage form, comprising:
i) a combination of the two active pharmaceutical ingrédients, dexketoprofen as a sait with organic or inorganic bases and tramadol as a sait with organic or inorganic acids, wherein:
the organic or inorganic base is selected from the group consisting of trometamol, trimethylamine, dimethylamine, ethylamine, trimethylamine, diethylamîne, Llysine, L-arginine, diethanolamine, sodium hydroxide, the organic or inorganic acid is selected from the group consisting of hydrochloric, hydrobromic, phosphoric, sulfuric, methanesulfonic, benzenesulfonic, toluenesulfonic, acetic, propionic, malic, maleic, succinic, citric, L-tartaric, lactic, malonic, aspartic, glutamic;
ii) a Aller which is microcrystalline cellulose;
iii) a binder selected from the group consisting of maize starch, maîze starch pregelatinized and hypromellose, or mixtures thereof;
iv) a pharmaceutically acceptable excipient.
2. A pharmaceutical composition according to claim 1, wherein the two active ingrédients form a homogeneous mixture in which said active ingrédients are intimately mixed.
3. A pharmaceutical composition according to claim 1, wherein the organic base is trometamol and the inorganic acid is hydrochloric acid.
4. A pharmaceutical composition according to claim 1, wherein said pharmaceutical excipient is selected from disintegrant, lubricant and glidant.
5. A pharmaceutical composition according to claims 1-4, contaîning a mixture of the two active ingrédients in a weight ratio of dexketoprofen to tramadol from 2:1 to 1:10, équivalent to a weight ratio of dexketoprofen trometamol to tramadol hydrochloride from 2.59:1 to 1:7.7.
6. A pharmaceutical composition according to claim 5, contaîning a mixture of the two active ingrédients in a weight ratio of dexketoprofen to tramadol from 1:1 to 1:6, équivalent to a weight ratio of dexketoprofen trometamol to tramadol hydrochloride from 1.3:1 to 1:4.63.
7. A pharmaceutical composition according to claims 1-4 contaîning the two active ingrédients, dexketoprofen and tramadol or salts thereof, in the following amounts for each oral dosage unit:
dexketoprofen from 8 to 50 mg, équivalent to dexketoprofen trometamol from
11.8 to 73.8 mg;
tramadol from 17.6 to 105.4 mg, équivalent to tramadol hydrochloride from 20 to 120 mg.
8. A pharmaceutical composition according to claim 7, containing the two active ingrédients, dexketoprofen and tramadol or salts thereof, in the following amounts, for each oral dosage unit:
dexketoprofen from 10 to 30 mg, équivalent to dexketoprofen trometamol from
14.8 to 44.29 mg;
tramadol from 26.3 to 87.8 mg, équivalent to tramadol hydrochloride from 30 to 100 mg.
9. A pharmaceutical composition according to claims 1-8, containing the two active ingrédients, dexketoprofen and tramadol or salts thereof, in the following spécifie amounts for each oral dosage unit:
dexketoprofen 12.5 mg or 25 mg, équivalent to dexketoprofen trometamol 18.45 mg or 36.95 mg;
tramadol 32.9 mg or 65.9 mg, équivalent to tramadol hydrochloride 37.5 mg or 75 mg.
10. A pharmaceutical composition according to claims 1-9, wherein microcrystalline cellulose is in a concentration range from 45 to 75% by weight of the total amount.
11. A pharmaceutical composition according to claims 1-10, wherein the bînder is selected from the group consisting of maize starch, maize starch pre-gelatinized and hypromellose or mixtures thereof, in amounts from 5% to 20%, preferably from 7% to 12% by the total weight of the composition.
12. A pharmaceutical composition according to claims 1-11, wherein the disintegrant is selected from croscarmellose sodium and sodium starch glycolate or mixtures thereof, in amounts from 4% to 14% by the total composition weight.
13. A pharmaceutical composition according to claims 1-12, wherein the dissolution of the two active ingrédients, dexketoprofen and tramadol, occurs in a time range not higher than 15 minutes, preferably between 3 and 11 minutes.
14. A pharmaceutical composition according to claims 1 to 13, wherein the dissolution rate and the purity profile of the components remain unchanged during shelf-life of 18 months at (25 ± 2)°C and (60 ± 5)% relative humidity in aluminium - aluminium and PVC/PVDC packages.
15. A pharmaceutical composition according to claims 1-14, which is in the form of tablet for immédiate release of the active principles.
16. A pharmaceutical composition according to claim 15, wherein said tablet comprises a hypromellose based outer film coating.
17. A pharmaceutical composition according to claim 15, comprising a polyvinyl alcohol based outer film coating.
18. A pharmaceutical composition according to claims 1-14, which is in the form of a capsule for the immediate-release of both active principles.
19. A pharmaceutical composition according to claims 1-18, for the treatment of acute pain related to the following conditions: headache, toothache, inflammations and migraine.
20. A method of manufacturing a pharmaceutical composition in accordance with claims 1 to
18, said method comprising fluid bed granulation and fluid bed drying of a mixture of active principles and excipients.
SXRi
ABSTRACT
PHARMACEUTICAL COMPOSITIONS CONTAINING DEXKETOPROFEN AND TRAMADOL
A pharmaceutical composition as a solid oral dosage form is described, comprising:
i) a combination of two pharmacological active principles, dexketoprofen sait with an organic or înorganic base and tramadol sait with an organic or inorganic acid, wherein:
the organic or inorganic base is selected in the group: trometamol, trimethylamine, dimethylamine, ethylamine, triethylamine, diethylamine, L-lysine, L-arginine, dîethanolamine, sodium hydroxide, calcium hydroxide the organic or inorganic acid is selected in the group: hydrochloric, hydrobromic, phosphoric, sulfuric, methanesulfonic, benzenesulfonic, toluenesulfonic, acetic, propionic, malic, maleic, succinic, citric, L-tartaric, lactic, malonic, aspartic, glutamic;
îi) microcrystalline cellulose as a filler;
iii) a binder selected in the group: maize starch, pre-gelatinised maize starch, hypromellose or their mixtures;
iv) pharmaceutically acceptable excipients.
Sheet 1/5
Figure 1
A) Dexketoprofen TRIS eleased amount [%] Released amount [%]
B) Tramadol HCl
Sheet 2/5
Figure 2
A) Dexketoprofen TRIS eleased amount [%] Released amount [%]
B) Tramadol HCl
Sheet 3/5
Figure 3
Released amount [%] Released amount [%]
A) Dexketoprofen TRIS
B) Tramadol HCl
Sheet 4/5
Figure 4
A) Dexketoprofen TRIS
Released amount [%] Released amount [%]
B) Tramadol HCl
Sheet 5/5
Figure 5
A) Dexketoprofen
Released amount [%]
Time [min.]
B) Tramadol
Time [min.]
SCB 1543 PCT 1/4
PCT REQUEST
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0 0-1 For receiving Office use only International Application No. PCT/EP2014/052342
0-2 International Filing Date 06 FEB 2014 ¢06.02.2014)
0-3 Namo of receiving Office and PCT Intemational Application' RO/EP
0-4 0-4-1 Form PCT/RO/101 PCT Request Prepared Using PCT Online Filing Version 3.5.000.235 MT/FOP 20020701/0.20.5.20
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The undersigned requests that the présent international application be processed according to the Patenl Coopération Treaty
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0-7 Appllcant’s or agents file reference SCB 1543 PCT
I Title of Invention PHARMACEUTICAL COMPOSITIONS DEXKETOPROFEN AND TRAMADOL CONTAINING
II Applicant
li-1 This person is Applicant only
II-2 Applicant for Ail designated States
II-4 Name LABORATORIOS MENARINI SA
II-5 Address Alfonso XII, 587 08918 BADALONA Spain
II-6 State of nation al ity ES
ΙΙ-7 State of résidence ES
111-1 Applicant and/or Inventor
111-1-1 This person is Inventor only
111-1-3 Inventor for
llt-1-4 Name (LAST, First) SCHMITZ, Reinhard
111-1-5 Address Glinicker Weg, 125 12489 BERLIN Germany
llt-2 Applicant and/or Inventor
111-2-1 This person is Inventor only
III-2-3 Inventor for
ΙΙ1-Ξ-4 Name (LAST, First) KOHL, Tobias
I1I-2-5 Address Glinicker Weg, 125 12489 BERLIN Germany
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IV-1 IV-1-1 IV-1-2 IV-1-3 IV-1-4 IV-1-5 IV-1-5(a ) Agent or common représentative; or address for correspondence The person identified below is hereby/ has been appointed to act on behalf of the applicant(s) before the competent International Authorities as: Name (LAST, First) Address Téléphoné No. Facsimile No. e-mail E-mail authorization The receiving Office, the International Searching Authority, the International Bureau and the International Preliminary Examining Aulhority are authorized to use this e-mail address, if the Office or Authority so wishes, 1o send notifications issued in respect of this international application: Agent BANFI, Paolo BIANCHETTI BRACCO MINOJA S.r.l. Via Plinio, 63 20129 MILANO Italy +39 02 76021218 +39 02 783078 mailbox@scb.it as advance copies followed by paper notifications
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FOR INTERNATIONAL BUREAU USE ONLY
11-1 Date of recelpt of the record copy by the International Bureau
...........-............. 17456
PATENT COOPERATION TREATY

Claims (6)

  1. From the INTERNATIONAL SEARCHING AUTHORITY
    To:
    Ban fi, Paofo
    Bianchetti Bracco Minoja S.r.l.
    Via Plin», 63
    20129 Milano
    ITALIE — RICEVUTO IL RECEIVED ON .
  2. 2 8 APR. 20H
    - BIANCHETTI BftUÇg MIN6JA eml.
    ’s file reference
    Applicant's or agent SCB1543 PCT
    International application No.
    PCTÆP2014/052342
    PCT
    NOTIFICATION OF TRANSMITTAL OF THE INTERNATIONAL SEARCH REPORT AND THE WRITTEN OPINION OF THE INTERNATIONAL SEARCHING AUTHORITY, OR THE DECLARATION (PCT Rule 44.1)
    Date of mailing (day/mpnthfyear·)
    24 April 2014 (24-04-2014)
    FOR FURTHER ACTION See paragraphs 1 and 4below
    International filing date (day/month/year)
    6 February 2014(06-02-2014)
    Applicant
    LABQRATORIOS MENARIN1 SA
    1. ΓχΊ The applicant is hereby notified that the international search report and the written opinion of tha International Saarching I—' Authority hâve been established and are transmitted herewith.
    Filing of asnendments and statement under Article 19:
    The applicant is entitled, if he so wishes, to amend the daims of the International Application (see Rule 46):
    When? The time limit for filing such amendments is normallytwo months from the date of transmittalof the International Search Report.
    Where? Directly to the International Bureau of W1P0,34 chemin des Colombettes
    1211 Geneva20, Switzerland, Fascimile No.: (41-22) 330.02.70
    For more detailed Instructions, see PCTAppllcant's Guide, International Phase, paragraphs 9.004 -9.011.
    2. I I The applicant is hereby notified that no international search report will be established and that the déclaration under I—’ Article 17(2)(a) to that effect and the written opinion of the International Saarching Authority ara transmitted herewith.
  3. 3. I I With regard to any protest against payment of (an) additional fea(s) under Rule 40.2, the applicant is notified that:
    the protest together with the decision thereon has been transmitted to frie International Bureau together with any request to forward the texte of both the protest and the decision thereon to the designated Offices.
    no decision has been made yet on the protest; the applicant will be notified as soon as a decision is made.
  4. 4. Reminders
    The applicant may submit commenta on an informai basison the written opinion of the International Search ing Authority to the international Bureau. The International Bureau will send a copy of suoh commenta to ail designated Offices unless an international prellminary examination report has been or is to be established. Following the expiration of 30 montha from the priority date, these commenta will also be made available to the public.
    Shortiy after the expiration of 18 months from the priority date, the international application witl be published by the International Bureau. If the applicant wishes to avoid or postpone publication, a notice ol wühdrawal of the international application, or of the priority claim, must reach the International Bureau before completion of the technioal préparations for international publication (Rules 9CN6.1 and 9 Obis.3).
    Within 19 months from the priority date, but only in respect ofscme designated Offices, a damand for international preliminary examination must be filed if tha applicant wishes to postpone tha entry into the national phase Until 30 monthsfrom the priority date (in some Offices avec later); otherwise, the applicant must, Within 20 months from the priority date, perform tha prescribed acte for entry into the national phase before those designated Offices.
    In respect of other- designated Offices, the time limit of 30 months (or later) will apply even if no demand is filed within 19 months.
    For details about the applicable time limita, Office by Office, see www ,wîpo.int/pct/enAextsrti me_limits.html and the PCT Applicant^ Guide, National Chapters.
    Name and mailing address ofthe International Saarching Authority European Patent Office, P.B. 5818 Patentlaan 2 NL-2280 HV Rijswijk .Siffl Tel. (+31-70)340-2040 'ΛΰΡ Fax: f-t-31 -7m Α4Π-3Π1R Authorized office r HOHMANN, Birgit Tel: +49 (0)89 2399-6798
    Form PCT/ISA/220 (July 2010)
    I
    PATENT COOPERATION TREATY
    PCT
    INTERNATIONAL SEARCH REPORT (PCT Article 18 and Rules 43 and 44)
    Applicant’s or agent's file reference SCB1543 PCT FOR FURTHER see Form =qt/isa/220 ACTION 33 as> where applicable, item 5 below. International applioation No. PCT/EP2014/052342 International filing date (day/monWyear) 6 February 2014 (06-02-2014) (Eariiest) Priority Date (day/month/yaar) 14 February 2013 (14-02-2013) Applicant LABORATORIOS MENARINI SA
    This international searoh report has been prepared by Bris International Searohing Authority and is transmitted to the applicant according to Article 18. Acopy is being transmitted to the International Bureau.
    This international searoh report consists of a total of_____________ί______sheets.
    |X | It is also accompanied by acopy of each prior art document cited in this report.
    1.
    Basisofthe report
    a. With regard to the language, the international searoh was carried eut on the basis of:
    ]~xl the international application in the language in which it was filed
    I I «translation of the international application into____________________________, which isthe language of a tranelation furnished for the purposes of international searoh (Rules 12.3(a) and 23.1 (b))
    This international searoh report has been established taking into account the rectification of an obvious mistake authorized by or notified tothis Authority urtder Rule 91 (Rule 43.6Ws(a)).
    b.
    c.
    With regard to any nucléotide and/or amino acid sequence disclosed in the international application, see Box No. I.
    2.
    Certain claims were found unsearchable (Sas Box No. Il)
    3.
    Unity of invention Is lacklng (see Box No 111}
    4.
    With regard to the title, [X~| the text is approved as submitted by the applicant | | the text has been established by this Authority to read as follows.
  5. 5.
    With regard to the abstract,
    0 the text is approved as submitted by the applicant | | the text has been established, according to Rule 38 2, by this Authority as it appears in Box No. IV. The applicant may, within one month from the date of mailing of this international searoh report, submit commenta to this Authority
    With regard to the drawings, the figure of the drawings to be published with the abstract ts Figure No._______________ | | as suggested by the applïoant [ | as selected by this Authority, because the applicant failed to suggest a figure [ | as selected by this Authority, because this figure better characterizes the invention
    Ξ no ne of the ligures is to be published with the abstract
    a.
    I
  6. 6.
    b.
    Form PCT/ISA/210 (first sheet) (July 2009) •Λ
    I
    International application No
    PCT/EP2014/O52342
    INTERNATIONAL SEARCH REPORT
    A. CLASSIFICATION OF SUBJECT MATTER
    INV. A61K31/135 A61K31/192
    ADD.
    Acoorriir.g te International Patent Classifioaiion (iPC) or to both national dassifcatian and IPC
    B. FIELDS SEARCHED_________________________________________________
    Minimum documentation searchad (olassifloûtion system followed by classification symbole)
    A61K
    Documentation searahed other than minimum documentation to the extent that such documents are included in the tie'ide tearched
    Electronic data bas* consulter! duréig the International search (nome of date base and, where practicabte, searoh terms used)
    EPO-Internal, MPI Data, BIOSIS, EMBASE
    C. DOCUMENTS CONSIDERED TO BE RELEVANT
    Category' Citation of document, with indication, where appropriate, of the relevant passages Relevant ta daim No. X WO 2008/150324 Al (THERAQUEST BIOSCIENCES INC [US]; BABUL NAJIB [US]) 11 December 2008 (2008-12-11) claims 1, 85 1-20 X WO 2008/092219 A2 (1NCREMENTHA PD & I PESQUISA DE [BR]; SUZUKI HENRY JUN [BR]; JUNIOR DAN) 7 August 2O08 (2008-08-07) claims 1-16 examples 1-5 1-20
    0 Further documents are listed In the continuation of Box C.
    * Spécial categories of ctsd documente ;
    Ά' document defining the general state of the art which te net consîdered to be of particular retevance
    Έ' earlter application or paient but publtehed on or after the international filng date
    Έ' dooumerrt whksh may throw doubts on priartty olalmfs) or which te cited toestablfsh the piîlioation date of another oitation or ether spécial reason (as specified) ’O document referrmg te an oral dsotosure, use, exhibition or other means 'P' document publtehed prier to the international filing date but later than the priority date claimed |X | Seepatentfamilyannex.
    Date ofthe actuel oompletion ofthe international search *T* later document publtehed after the International fiQng date or priority date and not In confiâtwith the application but cited to underatend the principle ortheory underlying the invention *X' documentof particularrelevanoe;thedaimedinvention oannotbe oonsidered novel or cannot be consîdered to involve an Inventive step when the document te taken alone
    Y document of particular relevanoe; the claimed invention cannot be consîdered to invdve an Inventive step when the document la combined with one or more other eue h documente, such combination being obvbus to a pereon skïled In the art document member of the same patent family
    Dateof mailing ofthe International search report
    14 April 2014
    24/04/2014
    Autho ri zed office r
    Name and mailing address ofthe ISA/
    Européen Patent Office, P.B. 5818 Patentlaan 2
    NL-2280 HV Rijswijr
    Tel. (+31-70) 340-2040,
    Fax: (+31-70) 340-3016
    Schifferer, Hermann
    Form PCTOSW210 (second sheet) (April 2005) page 1 of 2 i
    INTERNATIONAL SEARCH REPORT
    International application No
    PCT/EP2014/O52342
    C(Continuation). DOCUMENTS CONSIDERED TO BE RELEVANT Catagory' Cïetion of document, wïh indication, where appropriate, ofthe relevant passage» Relevant to claim No. X MIRANDA-H-F. PU1G-M-M. ROMERO-M-A. PRIETO-J-C.: “Effects of tramadol and desketoprofen on analgesia and gastrointestinal transit in mice, FUNDAMENTAL & CLINICAL PHARMACOLOGY, vol. 23, 1 January 2009 (2009-01-01), pages 81-88, ΧΡ0Θ2699340, page 82, left-hand column, line 2 - page 85, left-hand column, line 12 1-20
    Form PCT/ISA/21Û (continuâtron of second sheet} (Aprll 2005] page 2 of 2
    INTERNATIONAL SEARCH REPORT
    Information on patent lamily members
    International application No
    PCT/EP2O14/052342
    Patent document cited in search report Publication date Patent farrtily member(s) Publication date WO 2008150324 Al 11-12-2008 ΝΟΝΕ WO 2008092219 A2 Θ7-Ο8-20Ο8 AR 065068 Al 13-05-2009 BR ΡΙΟ70Θ133 A 16-09-2008 CL 2272008 Al 08-08-2ΘΘ8 C0 6210807 A2 20-10-2010 EC SP099596 A 29-09-2009 EP 2117519 A2 18-11-2009 JP 5441117 B2 12-03-2014 JP 2010516789 A 2Θ-Θ5-201Θ PE 16372008 Al 22-11-2008 US 2010062060 Al 11-03-2010 W0 2008092219 A2 07-08-2008
    Form PCT/ESAÆ10 (patent family annex] (April 2005)
    PATENT COOPERATION TREATY
    From the
    INTERNATIONAL SEARCHING AUTHORITY
    To: see form PCT/ISA/220 PCT WRITTEN OPINION OF THE INTERNATIONAL SEARCHING AUTHORITY (PCT Rule 43£>/s.1) Date of mailing (daydnonthfyear) see form PCTXSASIO (second sheet) Applicant's or agent’s file reference see form PCT/ISA/220 FOR FURTHER ACTION See paragraph 2 below International application No. PCT/EP2014X352342 International filing date (daydnonthÿear) 06.02.2014 Priority date (daydnonth/year) 14.02.2013
    International Patent Classification (IPC) or both national classification and IPC INV. A61K31/135 A61K31/192 i !
    Applicant
    LABORATORIOS MENARINI SA
    1. This opinion contaîns indications relating to the following items:
    Ξ Box No. I □ Box No. Il □ Box No. III □ Box No. IV □ Box No. V □ Box No. VI □ Box No. Vil □ Box No. VIII
    Basis ofthe opinion
    Priority
    Non-establishment of opinion with regard to novelty, inventive step and industrial applicability Lackofunityof Invention
    Reasoned statement under Rule 43b/s.1(a)(i) with regard to novelty, inventive step and industrial applicability; citations and explanations supporting such statement
    Certain documents cited
    Certain defects in the International application Certain observations on the international application
    2. FURTHER ACTION
    If a demand for international preliminary examination is made, this opinion will usually be considered to be a written opinion of the International Preliminary Examining Authority (IPEA) except that this does not apply where the applicant chooses an Authority other than this one to be the IPEA and the chosen IPEA has notifed the International Bureau under RuleS6.1bis(b) that wrîtten opinions of this International Searching Authority will not be so considered.
    If this opinion is, as provided above, considered to be a wrîtten opinion of the IPEA, the applicant is invited to submit to the IPEA a written reply together, where appropriate, with amendments, before the expiration of 3 months from the date of mailing of Form PCT4SA220 or before the expiration of 22 months from the priority date, whichever expires later.
    For further options, see Form PCTXSA/220.
    Name and mailing address of the ISA:
    Eurapean Paient Office
    D-80298 Munich
    Tel.+49 89 2399 -0
    Fax: +49 89 2399 · 4465
    Date of comptetion of this opinion see form
    PCT4SA210
    Authorized Officer
    Schifferer, Hermann
    Téléphoné No. +49 89 2399-7472
    Form PGTASAS37 (Cover Sheet) (July 2009)
    WRITTEN OPINION OF THE International application No.
    INTERNATIONAL SEARCHING AUTHORITY PCT/EP2014/052342
    Box No. I Basis of the opinion
    1. With regard to the language, this opinion has been established on frie basis of:
    ® the international application in the language in which it was filed □ a translation of the international application into , which is the language of a translation furnished for the purposes of international search (Rôles I2.3(a) and 23.1 (b)).
    2. □ This opinion has been established taking into account the rectification of an obvious mistake authorized by or notified to this Authority under Rule 91 (Rule 43bis. 1 (a))
    3. With regard toany nucléotide and/oramino acid sequence disclosed in the international application, this opinion has been established on the basis of a sequence listing filed or furnished:
    i.
    a. (means) □ on paper □ in eiectronic form
    b. (time)’ □ in the international application as filedi □ together with the international application in eiectronic form □ subsequently to this Authority for the purposes of search
    I
    4. □ In addition, in the case that more than one version or copy of a sequence listing has been filed or furnished, | the required statements that the information in the subséquent or additîonal copies is identical to that in the , application as filed or does not go beyond the application as filed, as appropriate, were furnished.
    5. Additîonal comments:
    Box No. V Reasoned statement under Rule 43b/s.1(a)(i) with regard to novelty, inventive step or industrial applicability; citations and explanations supporting such statement
    1. Statement
    Novelty (N) Yes: Claims No: Claims 1-20 Inventive step (IS) Yes: Claims No: Claims 1-20 Industrial applicability (IA) Yes: Claims No: Claims 1-20
    2. Citations and explanations see separate sheet
    Form PC77ISA/237 (April 2007)
    WRITTEN OPINION OF THE International application No,
    INTERNATIONAL SEARCHING
    AUTHORITY (SEPARATE SHEET)_______________________PCTÆP2014/052342
    Item V
    1. Documents
    The following documents D1-D3 are referred to in this communication; the numbering will be adhered to in the rest of the procedure:
    D1 WO 2008/150324 A1 (THERAQUEST BIOSCIENCES INC [US]; BABUL NAJIB(USJ) 11 December 2008 (2008-12-11) D2 WO 2008/092219 A2 (INCREMENTHA PD & I PESQUISA DE [BR]; SUZUKI HENRY JUN [BR]; JUNIOR DAN) 7 August 2008 (2008-08-07) D3 MIRANDA-H-F. PUIG-M-M. ROMERO-M-A. PRIETO-J-C.: Effects of tramadol and desketoprofen on analgesia and gastrointestinal transit in mice, FU N DAMENT AL & CLINICAL PHARMACOLOGY, vol. 23,1 January 2009 ¢2009-01 -01 ), pages 81 -88, Unless otherwise specified, reference is made to the respective cited passages in D1 D3 (see the Search Report). 2. Novelty - Article 33(1) and (2) PCT
    2.1 ) D1 refers to the combined use of dexketoprofen and tramadol via parentéral !
    administration, wherein both agents are selected out of two lists. ‘
    D2 discloses a capsule comprising ketoprofen tablets and tramadol tablets, wherein cellulose is contained in the tablet nucléus comprising tramadol. Tablets may be coated with hypromellose. Other excipients are contained in the capsule formulation. i
    D3 discloses the combination of tramadol and dexketoprofen.
    2.2) There is no document published, which would show the combined intégration of tramadol and dexketoprofen in an oral solid composition comprising a filler and a binder as disclosed tn claim 1.
    Therefore, the subject-matter of claims 1-20 is considered as novel in the light of Article 33(1 ) and (2) PCT.
    3. Inventive Step - Article 33(1 ) and (3) PCT
    The problem to be solved was to find a formulation for combined intégration of tramadol and dexketoprofen leading to a reduced level of incompatibilities.
    1 1
    Form PCT/ISA/237 (Separate Sheet) (Sheet 1) (EPO-April 2Q05)
    WRITTEN OPINION OF THE INTERNATIONAL SEARCHING AUTHORITY (SEPARATE SHEET)
    International application No.
    PCT/EP2014/052342
    According to the Applicant the problem was solved with a pharmaceutical composition in a solid oral dosage form comprising 1 ) a combination of dexketoprofen (sait with organic or inorganic bases), 2) tramadol (sait with organic or inorganic acids), 3) a filler (namely cellulose), 4) a binder (namely maize starch, maize starch pregelatinized, hypromellose), 5) excipient.
    The examples focus on dexketoprofen trometamol and tramadol hydrochloride, whilst an extended range of organic or inorganic bases in terms of dexketoprofen and organic or inorganic acids in terms of tramadol are claimed for the formation of salts. Stability and reduced risk of incompatîbility has not been investigated. Therefore, it has not been shown whether the problem as originally posed has indeed been solved.
    D2 could be taken as closest prior art, since already focusing on the combined use of tramadol and ketoprofen (dexketoprofen is the S enantiomer of ketoprofen), wherein optimal efficacy and safety profile hâve already been taken into considération.
    The type of inactive ingrédients as suggested in claim 1 has already been disclosed in some examples of D2.
    The examples lack to support a surprising or unexpected effect.
    From this point of view, the technical objective problem is to look for an alternative to D2.
    Compositions as disclosed in présent application are obvious to the person skilled in the art.
    Therefore, the subject-matter of claims 1-20 is not considered inventive according to Article 33(1) and (3) PCT.
    Form PCT/ISA/237 (Separate Sheet} (Sheet 2} (EFO-April 2005)
OA1201500313 2013-02-14 2014-02-06 Pharmaceutical compositions containing dexketoprofen and tramadol. OA17456A (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
ITMI2013A000210 2013-02-14

Publications (1)

Publication Number Publication Date
OA17456A true OA17456A (en) 2016-12-22

Family

ID=

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