Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
  • A61J3/00—Devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms
  • A61J3/007—Marking tablets or the like
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
  • A61J3/00—Devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
  • A61J2205/00—General identification or selection means
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B41—PRINTING; LINING MACHINES; TYPEWRITERS; STAMPS
  • B41M—PRINTING, DUPLICATING, MARKING, OR COPYING PROCESSES; COLOUR PRINTING
  • B41M5/00—Duplicating or marking methods; Sheet materials for use therein
  • B41M5/24—Ablative recording, e.g. by burning marks; Spark recording
• • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
  • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
  • Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
  • Y10T428/00—Stock material or miscellaneous articles
  • Y10T428/24—Structurally defined web or sheet [e.g., overall dimension, etc.]
  • Y10T428/24355—Continuous and nonuniform or irregular surface on layer or component [e.g., roofing, etc.]
• • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
  • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
  • Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
  • Y10T428/00—Stock material or miscellaneous articles
  • Y10T428/24—Structurally defined web or sheet [e.g., overall dimension, etc.]
  • Y10T428/24479—Structurally defined web or sheet [e.g., overall dimension, etc.] including variation in thickness

Definitions

• the invention relates to a marked solid pharmaceutical form, and a laser marking method for producing this form.
• Such laser marking is invisible to the naked eye, but can be revealed by light microscopy. It is a means of effective fight against counterfeiting.
• Counterfeiters endanger the safety of the patient, who can be treated with a product that does not include any active ingredient and therefore has no beneficial effect. At worst, the patient may be treated with a product having adverse effects.
• the suspect product can be authenticated for example by analysis of the composition of the product, but such an analysis is slow and expensive.
• an authentic product can come from different sources, which complicates this detection.
• the laser marking of pharmaceutical tablets is described in the document WO 2009/051794.
• This network is intended to be revealed later by Moiré effect, during the superposition of a revealing layer.
• the grating is made by ablation of a part of the surface that can be performed by laser.
• the dimensions of the network are of the order of one micrometer, and in particular the depth of the ablation is between 50 nm and 5 micrometers ( ⁇ ).
• the invention advantageously makes it possible to provide an effective solution to the fight against counterfeiting, and to overcome the disadvantages of the methods and devices of the prior art.
• the invention makes it possible to propose an anti-counterfeiting solution that meets the needs of the pharmaceutical industry in terms of cost, efficiency, and ease of implementation, both in characterization and in detection.
• one of the objects of the invention is a marked solid pharmaceutical form comprising at least one continuous groove marking its surface, said groove being of depth lying in a range from 10 ⁇ to 100 ⁇ , preferably from 20 ⁇ to 50 ⁇ . ⁇ .
• the groove furthermore has a width in the range of from 5 ⁇ to 120 ⁇ , preferably from
• the groove forms a closed continuous line.
• the groove is preferably of length lying in the range 250 m to 3 mm, preferably 250 ⁇ to 500 ⁇ .
• the surface of the pharmaceutical form has a mean depth of roughness in the range of 10 ⁇ to 40 ⁇ , preferably 20 ⁇ to 40 ⁇ .
• the pharmaceutical form generally comprises at least two grooves each forming a closed continuous line.
• the pharmaceutical form comprises at least two grooves, each groove being separated from another groove by a distance of at most 100 ⁇ .
• the groove forms a marking pattern invisible to the naked eye, and not perceptible to the touch.
• the groove is part of a side square comprised in a range of 100 ⁇ to 250 ⁇ , preferably from 200 ⁇ to 250 ⁇ .
• the pharmaceutical form according to the invention is preferably selected from the group consisting of sticks, tablets, capsules, chewing gums and granules, preferably selected from the group consisting of tablets.
• the invention also relates to a method for labeling at least one solid pharmaceutical form according to the invention, said method comprising the formation of at least one groove by ablation of the surface of the solid form by means of a laser beam, said method being such that laser ablation is performed with laser energy in the range of 0.1 mJ / mm 2 to 500 mJ / mm 2 , preferably in the range of 0.1 mJ / mm 2 to 250 mJ / mm 2 .
• the marking method comprises providing a source of laser beam, providing means for optically guiding the laser beam to the surface of the shape, providing relative displacement means between the shape and the radius. laser, and producing a continuous groove on the surface of the shape by means of laser ablation by the laser beam and by means of the relative displacement of the surface and the laser beam.
• the optical guiding means preferably comprise a focussing lens, focal length even more preferably selected from the group consisting of 50 mm, 60 mm and 100 mm.
• the laser beam is of pulse duration from 100 fs to 50 ns and energy per pulse from 0.1 ⁇ to 100 ⁇ .
• an infrared laser with a pulse duration of 100 to 1000 fs, energy per pulse of 0.1 ⁇ to 100 ⁇ , preferably of 0.1 ⁇ to 30 ⁇ , and of length waveform in the range of 1000 to
• a laser with a wavelength of 1030 nm is used.
• an ultraviolet laser of pulse duration of 5 to 50 ns, of energy per pulse of 1 to 100 ⁇ , preferably 3 ⁇ to 100 ⁇ , and of wavelength within a range of 10 to 380 nanometers.
• a laser with a wavelength of 266 nm is used.
• the laser guiding means comprise at least one means for separating the laser beam into a plurality of secondary rays so as to form, preferably simultaneously, several continuous grooves on the surface of the pharmaceutical form.
• the invention finally relates to a packaging article comprising at least one pharmaceutical form according to the invention.
• the pharmaceutical form is marked (or etched) by the groove (or incision).
• the depth of the groove can be measured by atomic force microscopy, but such a measurement is difficult to perform.
• the groove depth according to the invention is such that the groove does not cross a coating (or coating) of the pharmaceutical form.
• the depth of groove measurement can be carried out by marking, according to a given parameterization, a film-coated, film-coated tablet, typically of thickness 50 ⁇ or 100 ⁇ . If the film has not been traversed by the marking, the groove depth is in one of the ranges according to the invention.
• the marking thus parameterized can then be used on a naked tablet or on a film-coated tablet.
• the width of the groove is measurable by scanning electron microscopy, the measurement accuracy being generally + or - 5%.
• marking is performed by laser ablation, the characteristics of the laser beam and the marking conditions allow the skilled person, if he considers it necessary, to establish a link between the width of the groove and the depth of the groove .
• pharmaceutical form (or “drug form” or “dosage form”) is meant according to the invention any form in which are put at least one active ingredient and at least one excipient (inactive material) to form a drug.
• a medicine is a substance used to prevent and / or treat, usually treat, a disease. This pharmaceutical form generally corresponds to the final physical appearance of the drug as it will be used in a patient.
• a pharmaceutical form is "solid” according to the invention, if it is limited by stable surfaces.
• continuous is understood to mean a groove realized point by point, the points being sufficiently close together so that, in observation at the furrow scale, one has the impression of a continuous groove.
• Each point is usually the result of laser ablation through a laser beam pulse. This advantageously makes it possible, in the context of the invention, to obtain the sharpness of the pattern created by the continuous groove or grooves. It would be possible to define the "continuous" groove by a maximum tolerance on the differences in groove depth: eg depth deviation of 5 to 20%, preferably 5 to 15%, over the entire length of the groove.
• the pharmaceutical form of the invention is such that the dissolution profiles of the unlabeled pharmaceutical form and of the labeled pharmaceutical form are almost identical.
• the marked dissolution profiles of a tablet are not modified with respect to the dissolution profile of the unlabeled tablet due to the marking operation.
• the pharmaceutical form according to the invention is such that the groove forms a marking pattern invisible to the naked eye, and not perceptible to the touch.
• invisible to the naked eye is meant according to the invention, not perceptible to human vision without technical assistance. This technical aid is typically a microscope. In general, an object of greater dimension less than about 100 ⁇ is considered invisible to the naked eye.
• this marking makes it possible to distinguish said pharmaceutical form from counterfeit products by virtue of the use of an optical microscope, generally at a magnification of 20 or 100. This makes it possible to have a pharmaceutical form specially adapted to the fight anti-counterfeiting.
• the furrow is in a side square within a range of 100 ⁇ to 250 ⁇ , preferably from 200 ⁇ to 250 ⁇ .
• the skilled person is able to achieve the marking pattern so that the marking remains invisible to the naked eye, and not perceptible to the touch, for example taking into account the width of the groove and the size of the square in which the motif is inscribed.
• the groove is generally located on a portion of the outer surface of the pharmaceutical form, this portion being accessible and, in particular, visible.
• the location on the surface of the tablet of this part generally depends on the packaging in which may be present form. So, in the case the more usual of a substantially cylindrical compact of low height, the groove is preferably present on one of the surfaces of substantially circular shape, and not on the edge of this tablet.
• the dimensions of the groove according to the invention imply that the marking pattern produced by the groove is advantageously clean and precise.
• the pharmaceutical forms of the invention generally have a marking quality such that the marking pattern is not masked by the roughness of the surface of said shape.
• the marking pattern has a particularly long life.
• the groove preferably forms a closed continuous line.
• the length of the groove is preferably in the range 250 ⁇ to 3 mm, preferably 250 ⁇ 500 ⁇ . Because of the possibility of making a groove of very small width, the skilled person can achieve, in these ranges of length, a groove invisible to the naked eye, even with a length of a few tenths to a few millimeters.
• the surface of the pharmaceutical form has a mean depth of roughness in the range of 10 ⁇ to 40 ⁇ , preferably 20 ⁇ to 40 ⁇ .
• the pharmaceutical form according to the invention may comprise a continuous groove as it is visible, under the conditions indicated above, even when the surface of the pharmaceutical form is very rough, ie with an average roughness depth of about 40 ⁇ . .
• the average roughness depth (Rt) or average height of the roughness profile (Rz) is as defined in ISO 4287: 1998.
• Rt is the arithmetic mean of the individual profile heights over the evaluation length.
• Rz is the individual profile height which is, for a base length, the difference between the highest peak and the deepest hollow. According to the invention, five basic lengths are considered per evaluation length.
• the pharmaceutical form comprises at least two grooves each forming a closed continuous line.
• the pharmaceutical form comprises at least two grooves, each groove being separated from another groove by a distance of at most 100 ⁇ , for example included in a range of 10 m to 80 ⁇ .
• a distance is the shortest distance separating any point of a groove from any other point in another groove.
• the pharmaceutical form is generally selected from the group consisting of sticks, tablets, capsules, chewing gums and granules, preferably selected from the group consisting of tablets.
• tablettes are meant according to the invention coated tablets (or film) or not, effervescent or not, gastroresistant or not, immediate release or prolonged (or modified), to swallow or to use in the oral cavity, possibly soluble or dispersible, orodispersible tablets or oral lyophilisates.
• capsules is meant according to the invention soft-shell or hard-shell capsules (capsules), immediate release or prolonged (or modified), gastroresistant or not, and the tablets.
• the reason for the marking on the pharmaceutical form according to the invention is, for example, an anti-counterfeit logo, a text, or any form that the marking tool can perform.
• the invention also relates to a method for labeling at least one solid pharmaceutical form according to the invention, said method comprising the formation of at least one groove by ablation of the surface of the solid form by means of a laser beam, said method being such that laser ablation is performed with laser energy in the range of 0.1 mJ / mm 2 to 500 mJ / mm 2 , preferably in the range of 0.1 mJ / mm 2 to 250 mJ / mm 2 .
• the marking process according to the invention is of great precision since it allows the pharmaceutical forms according to the invention to be produced by marking them with any anti-counterfeit type motif such as a logo. This marking process is also of great clarity since the grooves of these marked pharmaceutical forms are visible under optical microscopy, from a magnification of 20.
• Such a marking method advantageously makes it possible to produce a marked pharmaceutical form according to the invention, the groove (s) being invisible to the eye naked and not perceptible to the touch, without modifying the pharmacological properties of said form.
• the marking method comprises the provision of a laser beam source, the provision of optical guidance means for the laser beam up to the surface of the shape, the provision of relative displacement means between the shape and the laser beam, and producing a continuous groove on the surface of the form by means of laser ablation by the laser beam and by means of relative displacement of the surface and the laser beam.
• the optical guiding means comprise a focusing lens, focal length preferably selected from the group consisting of 50 mm, 60 mm and 100 mm.
• the laser beam (or beam) is of pulse duration from 100 fs to 50 ns and energy per pulse from 0.1 to 100 ⁇ .
• the method is such that an infrared laser with a pulse duration of 100 to 1000 fs, energy per pulse of 0.1 to 100 ⁇ , preferably 0.1 to 100 ⁇ , is used. 30 ⁇ , and wavelength in the range of 1000 to 1,000 nanometers. In such a case, preferably, the laser has a wavelength of 1030 nm.
• the method is such that an ultraviolet laser with a pulse duration of 5 to 50 ns, energy per pulse of 1 to
• the laser has a wavelength of 266 nm.
• the laser guiding means comprise at least one means for separating the laser beam into a plurality of secondary rays so as to form a plurality of continuous grooves on the surface of the solid pharmaceutical form. Preferably the formation of the multiple grooves takes place simultaneously.
• FIG. 1 schematically represents an optical system forming part of a laser marking device according to the invention
• FIG. 2 schematically represents the laser marking device according to the invention comprising the optical system of FIG. 1.
• Figure 1 schematically shows an optical system 9 forming part of a laser marking device 1 according to the invention.
• the optical system 9 consists of parts 2, 3, 4, 5, 6, 7 and 8.
• a source 2 of laser beam emits a laser beam L which passes through the optical system 9.
• the laser beam L passes through an h / 2 blade or half-wave plate, 3, creating a phase shift of 180 °, that is to say say a delay of half a wavelength, then a polarizer cube 4 to modify the energy per pulse, and a ⁇ / 4 blade or quarter wave plate, 5, to have a polarization circular need for good homogeneity of ablation on both axes of laser scanning.
• a mirror 7 at 45 ° C then a mirror 7 at 45 ° C to a laser focussing piece 8 provided with a focusing lens (not shown) for targeting and concentration of the laser beam at the focal point.
• Figure 2 illustrates the device 1 for marking the tablet C of Figure 1.
• the device 1 comprises the optical system 9, and allows the marking of a tablet C by means of a targeted and entered laser beam 11, which is focused on the surface of the tablet C.
• the system Optical 9 comprises the source, the optical elements and the focusing elements of the laser.
• the tablet C is present in a cylindrical cavity 10 for positioning the tablet C in the laser field.
• the cavity 10 belongs to an aluminum tool (not shown) having cavities, for example 14 cavities, all identical with a diameter of 9.5 mm and a depth of 6 mm. This tool is able to be closed hermetically for transport by a transparent plastic cover.
• the relative movement of the surface of the tablet and the laser beam is here obtained by means of displacement of the tablet related to the tooling.
• control and detection of these displacements are linked to a control device, for example managed by software, which also analyzes the parameters of the laser source.
• the device 1 according to the invention was used to mark different tablets.
• the verification of the marking pattern which comprises two continuous grooves closed next to each other, was carried out by optical microscope.
• the labeling motif has been characterized by scanning electron microscopy (SEM).
• SEM scanning electron microscopy
• a dark pink film-coated tablet tablet C1, size LxWxH
• a white oblong tablet tablet C3, size Lxlxh
• the tests carried out consisted in marking the tablets by fixing the values of several parameters which are: the focal length of the focusing lens F (which corresponds to the diameter of the lens used), the energy per pulse E (linked to the power P and at the firing rate v), the scanning speed (speed of movement of the beam on the laser), and the wavelength ⁇ . All these settings of the laser beam can be summarized in a single parameter which is the energy per area.
• the purpose of these marking tests was to obtain, for each tablet, an anti-counterfeit marking invisible to the naked eye, not perceptible to the touch and visible under the microscope. The results of the various tests are summarized below.
• laser S-Pulse HP 2 Amplitude Systems
• Quadrupled Vanadate laser named Laser III.
• Pulse duration 500 fs
• Pulse energy used 1 - 100 ⁇
• Pulse duration 500 fs
• Lenses used Lens f-theta 50mm; Afocal x3
• a first marking test of a C1 tablet was performed with the laser I and a focal length of 60 mm.
• the laser beam was emitted at a rate of 100 kHz for a pulse energy of 100 nJ.
• the scanning speed of the C1 surface was 2000 mm / s.
• the energy per area was 1 mJ / mm2.
• This test was carried out on a pattern comprising two closed grooves separated from one another, an elliptical-like groove and a groove of roughly elliptical type.
• the shortest distance between these two furrows was about 10 ⁇ .
• the pattern was of size 100 x 90 ⁇ . This motif was invisible to the naked eye. By optical microscopy with an enlargement of 100, it was possible to visualize this pattern.
• the filming had a thickness of 50 ⁇ . After removal of the film coating after the test, by cutting the tablet with a microtome which made it possible to drop the film, it was possible to observe by scanning electron microscopy the integrity of the tablet and to check that the groove made by laser marking had not passed through the film coating layer.
• the laser beam was emitted at a rate of 20 kHz for a pulse energy of 3000 nJ.
• the scanning speed of the C1 surface was 25 mm / sec.
• the energy per surface was 240 mJ / mm 2 .
• a complete pattern size 190 x 150 ⁇ was engraved, as in Example 1A.
• a first marking test of a C2 tablet was performed with the laser I and a focal length of 60 mm.
• the laser beam was emitted at a rate of 100 kHz for a pulse energy of 100 nJ.
• the scanning speed of the surface of C1 was 200 mm / s.
• the energy per area was 5 mJ / mm 2.
• a complete pattern of size 200 x 180 ⁇ has been engraved, as in the example
• a second marking test of a C2 tablet was performed with the laser III and a focal length of 50 mm.
• the laser beam was emitted at a rate of 20 kHz for a pulse energy of 3000 nJ.
• the scanning speed of the C1 surface was 25 mm / sec.
• the energy per surface was 240 mJ / mm 2.
• a complete pattern of size 190 x 150 ⁇ has been engraved, as in the example
• EXAMPLE 3 White uncoated (C3) white tablet Example 3A.
• a first marking test of a C3 tablet was performed with the laser III and a focal length of 50 mm.
• the laser beam was emitted at a rate of 20 kHz for a pulse energy of 3000 nJ.
• the scanning speed of the C1 surface was 50 mm / sec.
• the area energy was 120 mJ / mm 2.
• the complete engraved pattern was 190 x 150 ⁇ , as in Example 1A.
• the laser beam was emitted at a rate of 100 kHz for a pulse energy of 100 nJ.
• the scanning speed of the C1 surface was 200 mm / sec.
• the energy per area was 2.5 mJ / mm2.
• the complete engraved pattern was of size 200 x 180 ⁇ , as in Example 1A.
• the average marking time is about 80 ms.
• This average marking time generally includes the time due to the processing of the information by the marking software and the time due to the marking itself. This could easily be optimized within the scope of the invention by using software dedicated to a particular pattern or by multiplying the number of laser beams by an optical system that multiplies the initial beam.

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• Health & Medical Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Medicinal Chemistry (AREA)
• Pharmacology & Pharmacy (AREA)
• Life Sciences & Earth Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Epidemiology (AREA)
• Medicinal Preparation (AREA)
• Thermal Transfer Or Thermal Recording In General (AREA)
• Laser Beam Processing (AREA)

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• 2010
  • 2010-11-03 FR FR1059063A patent/FR2966731B1/fr not_active Expired - Fee Related
• 2011
  • 2011-11-02 AR ARP110104058A patent/AR083682A1/es unknown
  • 2011-11-03 TW TW100140237A patent/TW201231091A/zh unknown
  • 2011-11-03 EP EP11802465.2A patent/EP2635246A1/de not_active Withdrawn
  • 2011-11-03 JP JP2013537188A patent/JP2013541580A/ja active Pending
  • 2011-11-03 WO PCT/FR2011/052565 patent/WO2012059693A1/fr active Application Filing
• 2013
  • 2013-05-02 US US13/875,762 patent/US20130244002A1/en not_active Abandoned

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