U.S. patent application number 10/481377 was filed with the patent office on 2004-08-26 for drug activation process and vibrational mill therefor.
Invention is credited to Bresciani, Massimo, Dobetti, Luca, Rabaglia, Leonardo.
Application Number | 20040166155 10/481377 |
Document ID | / |
Family ID | 11042807 |
Filed Date | 2004-08-26 |
United States Patent
Application |
20040166155 |
Kind Code |
A1 |
Dobetti, Luca ; et
al. |
August 26, 2004 |
Drug activation process and vibrational mill therefor
Abstract
The invention comprises a process for activating drugs by means
of high-energy co-grinding of the drug with a pharmaceutical
carrier, characterised by the use of a vibrational mill equipped
with means that regulate the vibration frequency. The process,
performed by modifying the frequency of vibration and keeping its
amplitude constant, produces drug/carrier composites with a
constant particle size in which the degree of drug activation
increases in proportion to the frequency applied. The invention
also includes a vibrational mill suitably modified to perform the
process described.
Inventors: |
Dobetti, Luca; (Trieste,
IT) ; Rabaglia, Leonardo; (Parma, IT) ;
Bresciani, Massimo; (Trieste, IT) |
Correspondence
Address: |
Mark P Levy
Thompson Hine
2000 Courthouse Plaza NE
10 W Second Street
Dayton
OH
45402-1758
US
|
Family ID: |
11042807 |
Appl. No.: |
10/481377 |
Filed: |
December 18, 2003 |
PCT Filed: |
June 3, 2002 |
PCT NO: |
PCT/EP02/06050 |
Current U.S.
Class: |
424/465 ;
241/16 |
Current CPC
Class: |
A61K 9/146 20130101;
B02C 17/14 20130101; A61K 9/14 20130101 |
Class at
Publication: |
424/465 ;
241/016 |
International
Class: |
A61K 009/20; B04B
015/04 |
Foreign Application Data
Date |
Code |
Application Number |
Jun 29, 2001 |
IE |
2001/0620 |
Claims
1. Process for activating a drug by co-grinding the drug with a
pharmaceutical carrier, said process being characterised in that:
grinding is performed in a vibrational mill equipped with means
designed to regulate the vibration frequency; the desired degree of
activation is obtained by varying the vibration frequency, while
the vibration amplitude is kept constant.
2. Process as claimed in claim 1, in which the vibration frequency
is comprised between 200 and 4500 rpm.
3. Process as claimed in claim 1, in which the vibration frequency
is comprised between 500 and 4000 rpm.
4. Process as claimed in claim 1, in which the vibration frequency
is b comprised between 700 and 3500 rpm.
5. Process as claimed in claims 1-4, in which the said means
designed to regulate the vibration frequency is a potentiometer
connected to the motor of the mill, which can be suitably regulated
by an operator.
6. Process as claimed in claims 1-5, in which the drug and carrier
are used, optionally pre-mixed, in proportions of between 12:1 and
0.5:1 by weight.
Description
FIELD OF INVENTION
[0001] This invention relates to the field of drug activation by
high-energy co-grinding. It comprises a process that produces
pharmaceutical composites with controlled activation and particle
size. It also comprises a vibrational mill specifically adapted for
the performance of this process.
PRIOR ART
[0002] The formulation and administration of drugs which are
slightly soluble or insoluble is one of the major problems that
arises in pharmaceutical research. Slightly soluble or insoluble
drugs often present insufficient absorption in the gastrointestinal
tract, and consequently a low level of bioavailability. As a
result, pharmaceutical formulations must contain large amounts of
such drugs, and need to be administered repeatedly during the day,
in order to maintain a plasma concentration with therapeutic
efficacy.
[0003] The factors that influence the solubility and dissolution
rate of molecules in water are associated with their
chemical-physical properties such as crystalline form, particle
size, surface area and wettability. If these parameters are
suitably modified, the chemical-physical properties can be modified
to aid the solubility of the molecule in water.
[0004] The mechanical/chemical activation by high-energy
co-grinding of crystalline drugs with inert substances (carriers)
is a technique that allows modification of the chemical-physical
properties of drugs and consequently improves their solubility in
water.
[0005] In particular, high-energy co-grinding:
[0006] enables the drug to be thermodynamically activated by
destructuring of the crystal and forming an amorphous phase and/or
nanocrystalline structures inside the carrier (Nakai et al. Chem.
Pharm. Bull. 25, 3340, 1977; Kawano et al. J. Pharm. Dyn. 5, S4,
1982), this process being defined as "activation" of the drug for
the sake of brevity;
[0007] reduces the size of the carrier particles containing the
active constituent, thereby contributing to increase the
dissolution rate of the drug.
[0008] The vibrational mill is one of the types of equipment most
often used for high-energy co-grinding.
[0009] For example, WO 9632931 discloses mechanically activated
composites obtained by co-grinding of poorly soluble pharmaceutical
substances and sodium starch glycolate, for example, in high energy
vibration mills.
[0010] The mill usually consists of a cylindrical chamber or
reactor clad with inert material, inside which high-density
grinding means are installed. The grinding means are bodies with a
given shape, weight, volume and surface area, present inside the
reactor in varying numbers but not attached to it; they are
consequently free to move in response to mechanical stresses
imparted outside the reactor by a vibrating mechanism. The grinding
means are usually cylindrical bodies with flat or curved
(dome-shaped) bases, made of high-density shockproof material,
typically metal or metal oxide, such as aluminium oxide, zirconium
oxide or steel.
[0011] To perform grinding, the mill is loaded with a preset
quantity of grinding means and grinding powder, and made to
vibrate. Grinding takes place by compression of the powder between
the surfaces of the various grinding means which undergo free
rotatory/vibratory movement.
[0012] The vibration mechanism is produced by an electric motor
fitted to the reactor, to which two eccentric counterweights are
attached in such a way that they can be regulated; the stresses
imparted to the reactor cause a rotary/vibratory movement of the
grinding means. The transfer of energy from the motor to the
grinding chamber therefore depends on the power of the motor and on
the weights and reciprocal positions of the two counterweights,
which determine the amplitude of vibration of the chamber. The
mills are constructed so as to vary the weight and reciprocal
positions of the counterweights (also called guide angles) and thus
modify the amplitude of vibration; the power of the motor is fixed
and constant (DM28L Food Grade Vibro-Energy Mill. Sweco
Manual).
[0013] The grinding process presents a considerable ability to
activate drugs as a result of its ability to incorporate the drug
into the carrier In the nanocrystalline or amorphous state (the
states with the greatest solubility and bioavailability), and at
the same time to reduce the size of the particles of drug/carrier
composite. However, the conventional co-grinding process
simultaneously leads to a reduction in the particle size of the
drug/carrier composite, and at the same time to an increase in the
level of activation of the drug. As a result, such a process can
generally produce drug/carrier composites with a high level of
activation and very fine particle size, but does not allow highly
activated composites with a medium or coarse particle size, for
example, to be produced. Nevertheless in some cases it is desirable
to obtain a highly activated drug while avoiding extensive
reduction of the final particle size of the drug-carries composite;
this is because excessively fine granulation can make it difficult
to process the substance when pharmaceutical formulations are
prepared. In other cases, when the maximum thermodynamic activation
(activation plateau) has been reached, it may be desirable to
further reduce the particle size of the composite without
prejudicing the intactness of the product (increase in mill
temperature and degradation of drug and/or carrier). These effects
and products cannot be obtained with the conventional co-grinding
process in view of the process characteristics analysed above.
There is consequently an unmet need for more selective co-grinding
processes, capable to produce pharmaceutical composites with a
controlled particle size and degree of activation of the drug, and
in particular to control these two parameters independently.
[0014] DE 4343742 describes a vibrational mill comprising an
inverter which regulates the vibration frequency.
SUMMARY
[0015] This invention is based on the finding that if, in a
co-grinding process, the vibration frequency imposed on the mill
(number of oscillations in time) is modified without varying the
amplitude of the vibration (extension of oscillation), the degree
of activation of the drug increases in proportion to the frequency
imposed, while the particle size of the end product of co-grinding
(drug/carrier composite) remains substantially unchanged.
[0016] The imposition of different vibration frequencies with the
same amplitude enables the drug particle size to be reduced without
reducing that of the final co-ground composite; it is therefore now
possible to obtain a far final co-ground composite; it is therefore
now possible to obtain a far wider range of combinations of degree
of activation and particle size of the composite than was possible
with conventional co-grinding.
[0017] The present invention relates to a process able to produce
pharmaceutical composites with controlled activation and particle
size, and a vibrational mill specifically adapted for the
performance of this process.
DESCRIPTION OF INVENTION
[0018] The subject of this invention is a process for activating a
drug by co-grinding of said drug with a pharmaceutical carrier,
said process being characterised in that:
[0019] co-grinding is performed in a vibrational mill equipped with
means for regulating the vibration frequency
[0020] the desired degree of activation is obtained by varying the
vibration frequency, while the vibration amplitude is kept
constant.
[0021] In this process, the degree of activation attained by the
co-ground drug increases in proportion to the vibration frequency
applied, while the particle size of the carrier-drug composite
obtained remains constant. Thus by adjusting the frequency and
keeping the amplitude constant, it is now possible to control the
degree of activation of the drug reliably, without affecting the
particle size of the end product of co-grinding.
[0022] For the purpose of this invention, "drug activation" means
the ability to reduce or eliminate the amount of drug present in
crystalline form by increasing its nanocrystalline and/or amorphous
fraction.
[0023] The working value of the amplitude of vibration is
preferably between 3 mm and 15 mm of shift, most preferably between
5 mm and 12 mm, measured on the axis perpendicular to the ground.
Small changes of the vibration amplitude (i.e. +/- 10%) do not
interfere with obtaining the results of the present invention.
[0024] Once the amplitude value has been set, various drug/carrier
composites with increasing degree of activation can be obtained by
increasing the vibration frequency; these increases in frequency
generate an increase in drug activation, while the particle size of
the final drug/carrier composite remains constant. The vibration
frequency is generated by and equal to the mill motor rotation
frequency or rate. By way of example but not of limitation, the
working frequency is generally between 200 and 4500 rpm, preferably
between 500 and 4000 rpm, most preferably between 700 and 3500 rpm;
the choice of specific working value depends on the degree of
activation required: the higher the frequency, the greater the
degree of activation.
[0025] The vibration amplitude can be set with known systems, for
example with suitable counterweights positioned in such a way as to
determine the amplitude of vibration of the grinding chamber. The
operating frequency is set by regulating the motor rotation
speed.
[0026] In the process to which this invention relates, the operator
acts in the opposite way to that known according to the prior art.
In conventional mills, the ideal activation conditions are sought
by regulating the position of the counterweights (search for ideal
vibration amplitude) with a fixed vibration frequency, determined
by the power of the motor, whereas in the process in accordance
with the invention, this research is performed at a constant
amplitude, by varying the frequency (rotation speed) of the motor
(search for ideal vibration frequency).
[0027] The process is performed by loading the mill with a suitable
amount of drug and carrier, optionally pre-mixed; preferably the
drug and carrier are introduced into the mill as two separate
powders. By way of example, proportions of the drug and carrier of
between 12:1 and 0.5:1 by weight, preferably between 5:1 and 1:1,
can be used. The grinding time is usually between 1 and 8 hours;
for each drug/carrier mixture a peak time (plateau) is present,
after which grinding is complete and activation will not increase
any further.
[0028] The carrier can be any solid pharmaceutical excipient, such
as cross-linked and non-cross-linked polymers; examples of these
products are: cross-linked polyvinylpyrrolidone (PVP-CL),
cross-linked carboxymethyl cellulose (croscarmellose), polacrilin
potassium, starch and its derivatives such as sodium starch
glycolate (SSG), cyclodextrin (in particular .beta.-cyclodextrin),
cellulose and its derivatives; non-polymeric carriers such as
silica and alumina can also be used. To ensure a higher level of
activation, cross-linked polymers are preferably used.
[0029] The present process can be performed with any solid drug.
The process of the invention is particularly advantageous for drugs
which are slightly soluble or insoluble in water, because the
phenomenon of activation is observed to the greatest extent in
these products. Drugs with particularly low solubility are defined
as "class II" and "class IV" drugs according to "FDA/CDER Guidance
for Industry. Waiver of in-vivo bioavailability and bioequivalence
studies for immediate-release solid oral dosage forms based on a
Biopharmaceutical Classification System. August 2000". By way of
example but not of limitation, these products include cox-2
inhibitors, antiinflammatory drugs such as nimesulide, piroxicam,
naproxene, ketoprofen, ibuprofen and diacerheine, antifungal drugs
such as griseofulvin, itraconazole, fluconazole, miconazole and
ketonazole, bronchodilators/anti-asthmatic drugs such as
zafrilukast, salbutamol, beclomethasone, flunisolide, clenbuterol,
salmeterol and budesonide, steroids such as estradiol, estriol,
progesterone, megestrol acetate, medroxyprogesterone acetate,
antihypertensive /antithrombotic/vasodilator drugs such as
nefedipine, nicergoline, nicardipine, lisinopril, enalapril,
nicorandil, celiprolol and verapamil, benzodiazepines such as
temazepam, diazepam, lorazepam, fluidiazepam, medazepam and
oxazolam, anti-migraine drugs such as zolmitriptan and sumatriptan,
antilipoproteinemic drugs such as fenofibrate, lovastatin,
atorvastatin, fluvastatin, and simvastatin, anti-viral /
antibacterial drugs such as tosufloxacin, ciprofloxacin, ritonavir,
saquinavir, nelfinavir, acyclovir and indinavir, immunodepressant
drugs such as tacrolimus, rapamycine and didanisine,
anti-histaminic drugs such as loratadine, antitumour drugs such as
etoposide, bicalutamide, tamoxifen, doclitaxel and paclitaxel,
anti-psychotic drugs such as risperidone, antiosteoporotic drugs
such as raloxifene, anti-convulsant drugs such as carbamazepin and
phenytoin, analgetic/narcotic drugs such as oxycodone, hydrocodone,
morphine and butorpanol, muscle relaxant such as tinazadine,
anti-ulcerative drugs such as famotidine. For the purpose of the
invention, the term "drug" includes any active constituent with
biological effects on man and/or animals; this term also includes
mixtures of two or more drugs.
[0030] For the performance of the present process, the Applicant
has developed and used a new mill which includes systems designed
to regulate the vibration frequency. This modified mill constitutes
part of the present invention. The system which regulates the
vibration frequency is generally constituted by a potentiometer (or
inverter) connected to the mill motor and suitably regulable by an
operator; via regulation of the motor rotation speed, the
potentiometer determines the vibration frequency imposed on the
chamber, and therefore the vibratory energy of the grinding means.
At the same time the oscillation capacity of the mil remains fixed
within the amplitude range originally set.
[0031] Substantially any commonly available potentiometer can be
used in the vibrational mill, provided that it is compatible with
the voltage and current intensity of the mill in question. In
general, it is useful for the potentiometer (inverter) to allow the
mill motor to rotate at a speed (vibration frequency) of between
200 and 4500 rpm, preferably between 500 and 4000 rpm, most
preferably between 700 and 3500 rpm.
[0032] The type of grinding means contained in the mill is not
crucial to the invention, and reference should be made to the means
commonly used in high-energy co-grinding as regards this aspect.
They are normally bodies with a cylindrical or cylindroid shape,
preferably with flat or convex bases. The dimensions of the
grinding means are proportional to the volume of the mill. By way
of example, means could be used in which the diameter and height
are between 0.4 and 3 cm, independently of one another, and
preferably between 0.6 and 1.3 cm. The grinding means are made of
high-density shockproof material (preferably with a density greater
than 3 g/cc), such as aluminium oxide, zirconium oxide or steel.
The grinding means are introduced into the mill in the quantities
normally used for this type of equipment; by way of example, the
grinding means occupy 20% to 90% of the total internal volume of
the grinding chamber. The mill forming the subject of the invention
is of pharmaceutical grade, namely a mill with a steel grinding
chamber and linings made of plastic materials approved for
pharmaceutical and/or food uses.
[0033] The process described here above can produce a variety of
drug/carrier composites with constant particle size and different
degrees of drug activation. This constitutes an evident advantage,
for example when the particle size must not be too fine in order to
avoid processing problems at subsequent stages, but a high level of
drug activation is desired. The variable-frequency process enables
the ideal ratio of the drug to be prepared in the amorphous,
nanocrystalline or crystalline phase, without modifying the ideal
particle size reduction kinetics, which could adversely affect the
co-grinding process (e.g. temperature increase) and/or the
subsequent processing stages (e.g. excessively fine particle size
and problems of powder flow). Regulation of grinding with the
potentiometer has the further advantage that it does not require
any blockage of the apparatus, and can consequently be performed
continuously during the process. This is impossible with
conventional mills, in which the modification (moving the
counterweights) requires interruption of the vibration and stoppage
of the process, involving the risk of uneven grinding.
[0034] This invention will now be illustrated by reference to the
following examples, which are given by way of example but not of
limitation.
EXPERIMENTAL PART
Methods
[0035] The percentage of the drug in the amorphous, nanocrystalline
or crystalline state was determined by differential scanning
calorimetry using a Perkin-Elmer DSC7 calorimeter. The percentage
of drug in the crystalline or nanocrystalline form is determined by
comparing the fusion enthalpies relating to the crystalline form
(at temperature Tm) and nanocrystalline form (at temperature
T<Tm) with the enthalpy of the totally crystalline drug (100%
crystallinity).
[0036] The titre of the drug included in the carrier is determined
by spectrophotometry (UV/visible spectrum) or HPLC.
[0037] The particle size of the activated carrier/drug composite is
expressed as the Specific Surface Area (SSA). The SSA is determined
by helium absorption (BET).
[0038] The standard deviation of the percentage of amorphous,
nanocrystalline and crystalline phase is 2%. The standard deviation
of the SSA values is 0.5 m.sup.2/g.
EXAMPLE 1
[0039] 600 g of nimesulide and 1800 g of .beta.-cyclodextrin are
placed in a Sweco DM3 vibrational mill together with 80 kg of
aluminium oxide grinding means. The co-grinding process is
performed at a vibration amplitude of 10 mm, measured on the
vertical axis, and at a vibration frequency of 1500 rpm (frequency
of motor).
EXAMPLE 2
[0040] 600 g of nimesulide and 1800 g of .beta.-cyclodextrin are
placed in a Sweco DM3 vibrational mill together with 80 kg of
aluminium oxide grinding means. The co-grinding process is
performed at a vibration amplitude of 10 mm, measured on the
vertical axis, and at a vibration frequency of 500 rpm (frequency
of motor).
EXAMPLE 3
[0041] 600 g of nimesulide and 1800 g of .beta.-cyclodextdn are
placed in a Sweco DM3 vibrational mill together with 80 kg of
aluminium oxide grinding means. The co-grinding process is
performed at a vibration amplitude of 10 mm, measured on the
vertical axis, and at a vibration frequency of 3500 rpm (frequency
of motor).
[0042] The results of examples 1-3 are set out in Table 1.
1TABLE 1 Kinetics of thermodynamic activation and increase in
Specific Surface Area (reduction in particle size) Process Example
1 Example 2 Example 3 time Amorph. Nanocr. SSA Amorph. Nanocr. SSA
Amorph. Nanocr. SSA (hours) (%) (%) Crystal (m2g) (%) (%) Crystal
(m2g) (%) (%) Crystal (m2g) 0 0 0 100 4.5 0 0 100 4.5 0 0 0 4.5 1
21 16 63 7.6 9 12 79 7.9 28 21 51 7.7 2 28 32 40 7.4 14 23 63 7.6
37 40 13 7.5 3 33 52 15 6.8 18 33 49 7.4 44 51 5 7.2 4 40 52 8 7.3
23 38 39 7.4 47 51 2 7.3
[0043] The data set out in Table 1 show different thermodynamic
activation kinetics at different vibration frequencies, while the
particle size reduction kinetics (increase in SSA) remain
substantially unchanged.
[0044] In particular, in the three examples, the SSA of the product
remains substantially constant, regardless of the frequency values
applied and the co-grinding time. Conversely, drug activation (% of
amorphous and nanocrystalline phase) increases in proportion to the
grinding frequency.
* * * * *