FI95117C - Apparatus and method for filling a long, narrow cavity with a small opening with fine particulate material - Google Patents

Description

95117 '#

Apparatus and method for filling a long, narrow and small orifice cavity with fine particulate material

The invention relates to a device for filling a long, narrow and small-bore cavity with fine particulate material, which device comprises a source of particulate material; a gas source; and a discharge port having an orifice adapted to face the opening of the cavity, there is a gap between the mouth of the discharge port and the opening of the cavity.

The invention also relates to a method for applying the device.

It is desirable to administer the pharmacologically active agent in finely powdered form to a patient. For example, antiasthmatic and other drugs have been administered orally by inhalation-based delivery devices.

One problem with the administration of finely powdered substances is that it is often necessary to accurately and reproducibly fill long and narrow cavities or holes in the dispensing device with a metered dose of the substance.

In this regard, a device has recently been developed for administering a finely powdered solid antibiotic therapeutic preparation to the pericardial sac of a patient suffering from peritoneal disease (U.S. Patent 5,000,258,886). The device includes a narrow tip portion that is small enough to fit in a root canal sac. The powdered therapeutic preparation is placed in a narrow channel at the tip and distributed from the tip to the dental root sac.

Filling the narrow channel of the root canal dosing device with a suitable amount of powdered therapeutic preparation has proven to be a difficult task because the opening through which the preparation must pass is small and because the hole to be filled is relatively long and ka-35 pea. In addition, since a standard dose of therapeutic preparation must be delivered to the root canal sac, the delivery device must be able to be filled in an accurate and reproducible manner.

One known way of filling a cylinder, such as a core, with a powdered substance, such as powder, involves placing the powder in a hopper and allowing gravity to feed it through the base of the hopper into the core. This method is not applicable in the case of filling the tooth root membrane dosing device described above because the hole to be filled is too narrow to allow the particles to flow through the gravity by gravity feed. In addition, this therapeutic preparation is hygroscopic and does not flow evenly.

Another way to open a long and narrow hole, such as a canal-root membrane dispenser channel, involves collecting the powder pile and repeatedly sealing the channel after the desired weight of drug has been added to the weight of the dispenser. However, this method is very time consuming and inaccurate.

It is an object of the present invention to provide a device for filling a long and narrow cavity or hole with a relatively small opening with a finely powdered material. Another object of the invention is a device capable of accurately filling a long and narrow hole or cavity in a device for delivering a unit dose amount of a pharmacologically active powdered substance.

The device according to the invention is characterized in that it * further comprises means for providing a gas flow, which are connected to a source of particulate material; means for suspending the particulate material in the gas stream, the means communicating with the discharge port; and an overflow device in communication with the gap, wherein upon discharge of the gas flow containing the suspended particulate material from the mouth, the suspended particulate material is ejected into the cavity until the cavity is filled to its extent with the particulate material and the gas exits through the gap into the overflow device.

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The gap between the discharge port and the cavity or hole opening should be a distance not more than twice the size of the discharge port orifice, preferably a distance of 0.2 to 2 times the size of the discharge port orifice. Since the density of the powder 5 is typically much higher than that of the gas, the gas can easily change direction and exit through the gap, while the powder, which is denser, continues into a long and narrow cavity or hole due to its inertia. The other end of the cavity or hole to be filled must be closed. In case 10 that equipment such as small pipes and hoses need to be filled, the other end may be temporarily closed until filling is complete. When the hole is filled, the excess powder is automatically discharged through the gap and can be recovered if desired. In the case of the present invention, the powder is recovered because it is a pharmaceutical product that is valuable and should be recorded.

The invention also relates to a method for filling a long, narrow and small-hole cavity with a fine particle-20 material, in which method a terial source and a gas source are used as particles to provide a gas flow; and arranging the cavity opening so as to face the mouth of the discharge stream of the gas stream discharging the suspended particulate material, but .. at a distance defined by the gap from which the method is characterized by continuously suspending the particulate material in the gas flow; and discharging the gas stream containing suspended particulate material from the orifice of the discharge port toward the opening of the cavity, the particulate material being ejected into the cavity until the cavity is .. filled to size with particulate material, and the gas is allowed to escape through the gap into the atmosphere.

Figure 1 shows a discharge port, a gap and a cavity or hole to be filled.

35 Figure 2 is a block diagram of the system controls.

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Figure 3 shows one embodiment of a filling device according to the present invention.

Figure 4 is a detailed view of the piping of the nozzle assembly.

Figure 5 is a detailed view of the nozzle housing.

Figure 6 shows a dispenser filled with a device according to the present invention.

Figure 7 shows a histogram of pharmaceutical powder 10 fill weights with a target fill weight of 4.5 milligrams.

Figure 8 shows one embodiment of a multi-unit dose powder dispenser of the type useful for use in medicaments that can be delivered by oral inhalation.

Figure 9 shows another embodiment of a filling device according to the present invention.

The filling device according to the present invention is particularly well suited for filling a long and narrow cavity or hole with a relatively small opening with a finely powdered substance. In the case of the present invention, narrow means a width of about 1 millimeter or less in diameter, and long means about seven millimeters or more in length. The cavity or hole to be filled may be of any cross-section, such as square, rectangular, circular or irregular in shape. The hole does not need to have a flat cross section. In the case of the present invention, a relatively small opening is considered to be about 1 millimeter or less in width, i.e., diameter. Like a cavity .. or a hole, the shape of the opening can take many forms.

The invention is particularly well suited for filling various dosing devices with doses of pharmacologically active substances determined by the dosing unit. In this regard, it is stated that the substance should be packaged in the cavity of the dispensing device so that it can be dispensed therefrom. The device of the present invention is particularly suitable for this type of filling because the powdered substances are not packed too tightly because they are conveyed by a moving gas flow. In addition, it is noted that cylindrical cavities are particularly suitable for filling with the present device because the cylindrical sleeves and cylindrical pistons provide reproducible cross-sections and volumes for dispensing. Cylindrical pistons are also well suited for dispensing the entire amount of material without leaving anything in the corners, etc. In the event that the cavity has more than one orifice, all but one should be temporarily closed during filling, or otherwise the particulate gas flow will exit through the other orifices and the cavity will not fill. ty. This temporary blockage can be easily removed and items such as small pipes or hoses filled.

The filling device of the present invention is particularly suitable for filling all types of finely powdered substances, such as pharmacologically active powdered substances. Among the pharmacological agents which can be finely powdered and thus suitable for carrying out the present invention are peptides and proteins. Specific examples of the latter include natriuretic factor, tumor necrosis factor, oxytocin, vasopressin, adrenocortisotropic hormone (ATCH), epidemic growth factor, tryosidins, plasminidines, renin, bracydine, angiotensin, enctorphins, enctorphins, enctorphins, renal plasminogen factor 30, cholecystokinin, melanocyte inhibitory factor, melanocyte stimulating hormone, neuropeptide γ, nerve growth factor, muramyldipeptide, thymopoietin, human growth hormone, porcine growth hormone, porcine growth hormone, sodium pentomidine ), arogastrone, pentagastrin, tetragastrin, gast- 95117 6 rhin, interferons, glucagon, somatostatin, prolactin, superoxide dismutosis, luthenating hormone releasing hormone (LHRH), H-5-oxo-Pro-His-Trp-Ser-Tyr-Dtrp- Leu-Arg-Pro-GlyNH2, H-5-Oxo-Pro-His-Trp-Ser-Tyr-3- (2-napht yl) -D-5 alanyl-Leu-Arg-Pro-Gly-NH2, luthenating hormone releasing factor (porcine), 6- [O- (1,1-dimethylethyl) -D-serine] -10-deglycinamide-2- (aminocorbonyl) hydrazide (9C1), luthenating hormone releasing factor (porcine), luthenating hormone releasing factor (porcine), 6- [O- (1,1-dimethylethyl-10L) -D-serine] -9- [N- ethyl L-prolinamide] -10-deglycinamide- (9C1), 6-D-leucine-9- (N-ethyl-L-prolinamide) -10-deglycinamide- (9C1) and their synthetic equivalents, variants and pharmacologically active parts as well as pharmacologically acceptable salts.

Other classes of compounds suitable for filling with the present device include penicillins, beta-lactam blockers, cephalosporins, guinolones, aminoglycodian antibiotics (gentamicin, tobramycin, kanamycin, amikacin), estradiol, norethisterone, norogindorene, norethindorene, norethindrone, tetracyclines (doxycycline, minocycline, oxytetracycline, tetracycline, chlorotetracycline, demeclocycline, metacycline) clindamycin, vitamin B-12, anesthetic (procaine, tetracaine, lidocaine, 25-cidine, medido) C, bleomycin, vinblastine, vincristine, cytosine, arabinoside, ARA-AC, actinomycin D, daunomycin, daunomycin benzoylhydrazone, nitrogen mustards, 5-azacytidine, calcium Leucovorin, cis-platinum compounds, 5-Fluorouracil, 5-Fluorouracil, maytansine, melphlan, mecatopurines, methyl CCNU, hexamethylmelamine, etoposide, hydroxyurea, levamisole, mitoquanzone, misonidazole, pentostatin, tenisposide, thioauqnime, dichloromethotrexate, chloroprothixene, molindone, loxapine, haloperidol, clo-35 ropromazine, triflupromazine, mesoridazine, thiori- 95en7 7-decicin, pharmaceutically acceptable salts, hydromorphone, oxymorphone, levorphenol, hydrocodone, oxcodone, nalophine, naloxone, naltrexone, bud-5 renorphine, butorphenol, nalbudhine, mepridine, alphaproprine, anileridine, dentenoxylate, diphenoxylate The above can be utilized in finely powdered form, with sizes of about 0.5 microns and larger. It should be noted, however, that the substances must not be so large as to impede suspension in the moving gas stream. In addition, useful agents include the microencapsulated pharmaceutical products described in U.S. Patent 5,000,886. These microencapsulated agents typically have a size of 20 to 120 microns in diameter, making them suitable for filling with the present device.

It is understood that the type of gas used to suspend the solid material must be compatible with the substance and, in the case of pharmaceutical products, must meet purity requirements. In this regard, keeping in mind compatibility and purity requirements, a great many gases could be used, including air, nitrogen, dry air, carbon dioxide, argon and others. 25 inert gases. Dry air or nitrogen is considered best in the case of hygroscopic or hydrophilic particles.

Referring to Fig. 1, a discharge port 1 having an orifice 4 of width or diameter D is positioned to indicate an opening of a dispensing device 3 having a cavity 2. The width or diameter of the opening 5 is X. The discharge port 1 is separated from the opening 5 of the cavity 2 by a gap G. The width or diameter D of the discharge port mouth must be equal to or smaller than the width or diameter X of the mouth 5 of the cavity 2 to be filled. - 8 95117 * If the mouth or cavity openings of the seasonal gates are irregular or different in size, it is desirable that the discharge port fit inside the cavity opening. If the width or diameter of the orifice 4 exceeds the width or diameter of the cavity 2, a large part of the particulate material suspended in the gas flow flows laterally into the cavity 3 and thus does not enter the cavity 2. The orifice 4 orifice 1 and device 3 orifice 5 are spaced apart by G. It has been found that a slit which is not more than 2 times the width or diameter of the mouthpiece 4 meets this criterion. Primarily, the gap G is a distance of 0.2 to 2 times the width, i.e. the diameter D. The width of the gap G should be large enough to allow the gas to escape, but not so large that the particulate material does not travel with the gas stream crossing the gap.

In the embodiment of the device described herein (Figures 2-4), the discharge port has an orifice diameter of about 0.0965 cm (0.038 inches) and a gap of about 0.0254 cm (0.010 inches).

It will be appreciated that the pulverized material may be suspended in the mobile gas stream by any device, such as a venturi device described in more detail herein, or by a fluidized bed or any other device that provides particles suspended in the mobile gas stream. However, the device in question must be able to sus-. 25 to pend a sufficient number of particles to fill the required cavities quickly and efficiently, but to prevent the suspension of too many particles so that the particles do not block the discharge port or gap. In this regard, for example, the gas flow rate through the device, such as a venturi, can be adjusted to maintain a proper suspension of particles in the gas flow.

In one embodiment, the filling device includes a reservoir for the powdered material to be filled, a gas source (dry air or nitrogen), a regulator to obtain the required volume flow rate, a venturi nozzle assembly 95117 9 to discharge the gas, and to draw the powder into the discharged gas flow. Optionally, it may also have an overflow collector to collect the powder left over from the volume needed to fill the narrow channel hole.

Referring to Figure 2, the gas supply 10 is controlled by a regulator 15 prior to connection to the solenoid controlled pneumatic valve 20. When the pneumatic valve 20 is actuated by a standard 115 volt source 25, the so-10 lenoid controlled valve opens to allow gas to flow through line 30 into the filling system. Since only a short gas discharge is required for the operation of the present invention, the adjustable timer relay 35 is set to limit the opening time of the solenoid-controlled pneumatic valve to less than one second. The gas supply is not required to be pulsating but is recommended to avoid packaging of the finely powdered material. The closing of the timer relay 35 is started by activating the closing of the switch 40.

The filling system is shown in more detail in Figure 3. The gas supply to the system 30 is shown in both Figures 1 and 2. The gas supply is connected to the venturi assembly 45 using a standard pneumatic connector 50. In the venturi assembly 45, the gas enters the piping 55 shown in both figures. 25 3 and 4. Referring to Figure 4, the powder supply tube 60 passes through the piping and acts as the backbone of the tube assembly. The collar 65 allows gas to enter the tube assembly through the orifice structure 70 and pass through the collection space 75 and exit through the orifices 80 in the orifice plate 85.

In this way, the gas is discharged through a plurality of orifices and surrounds the powder supply pipe 60.

The gas supply 30 of Figure 3 is divided in the T-connector 90 to go to both the nozzle assembly 45 and the powder supply 95, more specifically to the space above the powder, 35 marked 100. In pulsating mode, pressurizing the powder source 95117 10 causes powder dispensing to begin very quickly. Without this "pre-pressure", it would take several seconds for the venturi phenomenon to develop a useful powder flow. The suction tube 110 is immersed in the powder 105 and passes through the tubing assembly 5 to the nozzle assembly 45.

Figure 5 shows the nozzle housing 115. The gas supply enters through the cylindrical opening 120 and the piping is installed through the opening 125. A small, infillable cylindrical channel is placed in the cylindrical holding portion 130 and any overflow powder 10 exits through the overflow tube 135.

In operation, upon exiting the nozzle 80, the gas is forced to flow through the neck of the venturi area 140, which is determined by the clearance between the piping 115 and the powder supply pipe 60. Because the gas velocity is high through the venturi 140 15, the pressure in this region decreases sharply.

This low pressure region draws the powder 105 through the suction pipe 110, mixes the gas with the powder, and the gas / powder mixture exits through the discharge port 131. In operation, Fig. 3, a dispensing device with a filling cavity 145 is held in the holding portion 130 of the nozzle housing 115.

Slit G is critical to the operation of this device. The overflow pipe 135 allows excess gas and pulverized material to escape during the filling process. Operations. The velocity of the gas / powder mixture compresses the powder dose into the cavity of the roller 145, but a much lower density gas is able to change direction and exit through the gap G and the overflow tube 135.

A quantity of powder mixes with the overflow gas 30 and passes to the overflow collector 150. To prevent the overflow collector 150 from being pressurized, it has a ventilation opening 155 in the atmosphere. If the overflow collecting vessel 150 did not have a ventilation opening to the atmosphere, the pressure in the vessel would increase. As this pressure increases, it would reach a point 35 where the pressure used to transport the gas would be equal to the pressure of the overflow vessel. At this point there would be no pressure difference and thus no driving force. To prevent the refillable powder from contaminating the environment, the overflow collector has a filter 160 that prevents the powder from escaping and helps to recover the powder in applications where the powdered material is valuable.

Referring to Figure 6, the dispenser 200 is comprised of two parts, a sleeve 210 and a piston 220. In a preferred embodiment, exactly 4.5 milligrams of pharmaceutically active material is measured in the dispenser 200. A modified depth micrometer 230 is mounted to the block 240 so that when the micrometer screw is turned, the pin 235 moves inward or outward depending on the direction of rotation of the micrometer screw. The rod 235 15 is sized to easily fit into the dispenser sleeve 210. In use, the plunger 220 is pushed in and then the dispenser assembly is placed over the rod 235 to provide a fixed and reproducible position on the plunger 220 in the sleeve 210. If the amount of substance 20 is always fixed, micrometer adjustment is not required and can be replaced with a fixed length rod.

The embodiment shown in Figures 1-6 has been evaluated to determine if it accurately and precisely fills the cavity 250 of the dispenser 200. Figure 6 shows a typical histogram of fill weights for about 5400 fillings.

The x-axis of the histogram shows the fill weights of a 5400 tooth root membrane dispenser filled with antibiotic minocycline. The fill weights obtained are divided into 14 ranges from 3.9 milligrams to 5.2 milligrams in 0.1 milligram increments for presentation 30. The y-axis of the histogram shows the number of dispensers with the indicated fill weight.

It is evident that the fill weights are grouped 35 narrowly. In particular, the average fill weight is 4.5 95117 12 milligrams (which was the target fill weight), with a standard deviation of 0.19 milligrams. This standard deviation of 4.22% is acceptable in pharmaceutical applications.

The device described in this application can be used to fill other medication delivery devices that deliver powdered inhalants to the lungs. In particular, some medications are most effective when delivered directly to a patient’s lungs. Examples include drugs for reversible airborne information, such as asthma, drugs for lung diseases or inflammation, all drugs used to treat occasional pneumonia that infects patients with antibodies to the HIV virus (AIDS). Examples also include biotechnology polypeptide products.

Freeze-dried polypeptides can be administered via the lung. These rDNA products are very strong. And the doses required are likely to be small. The present invention is capable of accurately measuring small volumes of powdered drug into a dispenser for later use.

Figure 8 shows a device for storing multiple doses of powdered substance, which device is useful in drug delivery devices for delivering drug to the lungs. It consists of a support plate 800, preferably made of plastic or paper, with a mounting part 810 shown as a hole, but which may be any practical holding means, and which also has one or more long, thin, tubular devices 820a to 820n, holding one or more doses of the drug. The present kek-30 can be used to fill these tubular devices with a drug. Instruments must be made of a material that can be easily pierced or broken so that the entire contents of one instrument are available for therapy. The number of such devices is a design choice, but may readily comprise one (1) to thirty (11) doses. The device of the present invention can be used to fill one device at a time in preparation for closing the filled device, and then move the support plate 800 to place the next location, such as 820b, in the filling device.

Alternatively, it is practical to construct a filling device according to the present invention with a plurality of vents and a plurality of sources and slots, whereby all the devices on the plate 800 are filled simultaneously.

Fig. 9 is a variation of Fig. 2 in which the filling device of Fig. 2 is adapted to fill the dispensing device 820a instead of the small channel cylinder. The nozzle housing 115 has been modified so that the opening 130 in Figure 3 has been replaced by a notch 900. The support plate 15 800 can be rotated about an axis 910, whereby the devices 810a, 810b, 810c, etc. can be led to the discharge port.

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Claims (11)

An apparatus for filling a long, narrow and small orifice cavity with fine particulate material, the apparatus 5 comprising a) a source of particulate material (95), b) a source of gas, and c) a discharge port (1; 131) having an orifice (4) arranged to be oriented an opening of the cavity (2; 145) towards the cavity (5), the gap (G) between the mouth opening (4) of the discharge port (1; 131) and the opening (5) of the cavity (2; 145), characterized in that the device further comprises d ) means for providing a gas flow in communication with the particulate material source 15 (95), e) means for suspending the particulate material in the gas flow, the means communicating with the discharge port (1; 131), and f) an overflow device (135) connected to the gap (G), wherein upon discharge of the gas stream containing the suspended particulate material from the orifice (4), the suspended particulate material is ejected into the cavity (2; 145) until the cavity is filled to its extent with the particulate material , and the gas can escape through the gap (G) into the overflow device (135). Device according to Claim 1, characterized in that the width or diameter (D) of the opening (4) of the discharge port (1) is equal to or smaller than the width or diameter 30 (X) of the opening (5) of the cavity (2) to be filled. ). Device according to Claim 1, characterized in that the gap (G) is not more than twice the width or diameter (D) of the mouth opening (4) of the discharge port (1). 1 «95117 Device according to claim 1, characterized in that the means for suspending the particulate material in the gas flow comprise a venturi (140) and means (60, 110) for connecting the particulate material source (95) to the venturi. Device according to claim 1, characterized in that the means for suspending the particulate material comprise a fluidized bed. The apparatus of claim 1, characterized in that the apparatus further comprises a particulate material recovery system comprising a collection vessel (150) pneumatically connected to the overflow device (135), the collection vessel having an opening (155) communicating with the atmosphere by a particulate impermeable filter (160). ). Device according to Claim 1, characterized in that the gas is air, nitrogen or carbon dioxide. Device according to Claim 1, characterized in that the particulate material is a pharmaceutical compound. Device according to Claim 8, characterized in that the pharmaceutical compound is minocycline. Device according to Claim 1, characterized in that the gas source is arranged to pulsate for a period sufficient to fill the cavity (2; 145). A method of filling a long, narrow and small orifice cavity with fine particulate material, the method comprising a) using a particulate material source (95) and 30 gas sources to provide a gas flow, and b) fitting the cavity (2; 145) opening (5) to accommodate suspended particulate material the orifice (4) of the discharge stream (1; 131) discharging the gas flow, but at a distance defined by the gap (O), characterized in that 95117 c) the particulate material is continuously suspended in the gas flow, and d) the gas flow containing the suspended particulate material is discharged from the orifice 5 (4) of the discharge port (1; 131) towards the opening (5) of the cavity (2; 145), whereby particles - terlaall are ejected into the cavity (2; 145) until the cavity is filled to size with particulate material and the gas is allowed to exit the gap (G ) through the atmosphere. «· 17 95117