Patent Application
20080035667
For purposes of illustration, the drawings show selected, representative structures, it being understood that the invention is not limited to the precise arrangements and instrumentalities shown.
Like reference characters denote like elements throughout the drawings.
It will be appreciated that the following description is intended to refer to specific representative structures selected for illustration in the drawings and is not intended to define or limit this disclosure, other than in the appended claims.
The hopper can be connected to an apparatus for producing capsules or other dosage forms comprising a matrix and a pharmaceutically active agent. Thus, the liquid moving from the hopper to the capsule-producing apparatus can comprise a formulation which is liquid under certain conditions of temperature and/or pressure. Such liquid can solidify after it has been delivered from the hopper and processed by the capsule-forming apparatus.
Suitable formulations that can be delivered through the liquid supply system include those comprising a polymeric material which melts at a certain temperature, admixed with a pharmaceutically active agent. This agent can be dissolvable in the melted polymeric material, or it can form a suspension in the melted polymeric material. Suitable polymeric materials include polyalkylene (oxides) such as polyethylene glycol and propylene glycol, waxes such as paraffin, and polysaccharides of any suitable molecular weight. For Example, if PEG is used, suitable member average molecular weights include about 600, about 800, about 1000, about 3500, about 4000, about 6000, about 10,000 or about 100,000 Other suitable polymeric materials are apparent to those of ordinary skill in the art.
The liquid formulations that can be delivered through the liquid delivery system can further comprise other excipients commonly used in formulating solid drug dosage forms. Suitable excipients include sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, and methyl cellulose; powdered tragacanth; malt; gelatin; talc; solid lubricants, such as stearic acid and magnesium stearate; calcium sulfate; vegetable oils, such as peanut oil, cottonseed oil, sesame oil, olive oil and corn oil; sugar alcohols such as sorbitol and mannitol; emulsifiers such as polysorbate 60, polysorbate 80 and sodium lauryl sulfate; coloring agents; flavoring agents; tableting agents, stabilizers; antioxidants; preservatives; water insoluble polymers such as poly(vinyl alcohol), polypyrrolidone and poly(acrylic acid); disintegrants such as alginic acid and croscarmelose; lubricants such as magnesium stearate, stearic acid and talc; glidants such as silicon dioxide; coloring agents, such as the FD&C dyes; and sweeteners and flavoring agents such as aspartame, saccharin, menthol, peppermint, and fruit flavors. Other suitable excipients for formulating a liquid formulation for delivery through the liquid delivery system are apparent to those of ordinary skill in the art, as described for example in Remington's Pharmaceutical Science, 17th edit., Mack Publishing Company, Easton, Pa. (1985), the entire disclosure of which is herein incorporated by reference.
As discussed above, the liquid may further comprise any suitable pharmaceutical agents or agents for delivery in tablet or pill form. Examples of suitable pharmaceutically active agents include, but are not limited to, antibiotics such as the glycopeptide antibiotics, gentamicin, penicillin and its derivatives such as amoxicillin, and erythromycin; analgesics such as NSAIDs (e.g., aspirin and other salicylates, ibuprofen, naproxen, nabumetone and COX-2 inhibitors such as celecoxib), opioids and the like; and antivirals such as nucleic acid polymerase inhibitors (e.g. acyclovir, gancyclovir and valgancyclovir), ribavirin, amantadine, pleconaril and interferons; and combinations of these.
Suitable opioids include, but are not limited to, alfentanil, buprenorphine, butorphanol, codeine, dezocine, dihydrocodeine, fentanyl and fentanyl congeners (e.g., sufentanil, alfentanil, lofentanil, carfentanil, remifentanil, trefentanil, and mirfentanil), hydrocodone, hydromorphone, levorphanol, meperidine (pethidine), methadone, morphine, nalbuphine, oxycodone, oxymorphone, pentazocine, propiram, propoxyphene, tilidine, tramadol, the pharmaceutically acceptable acid addition salts thereof, and combinations of these.
As used herein, a “glycopeptide antibiotic” refers to oligopeptide (e.g., heptapeptide) antibiotics, characterized by a multi-ring peptide core optionally substituted with saccharide groups, such as vancomycin or vancomycin-B. Suitable glycopeptides for use in the liquid formulation include A477, A35512, A40926, A41030, A42867, A47934, A80407, A82846, A83850, A84575, AB-65, Actaplanin, Actinoidin, Ardacin, Avoparcin, Azureomycin, Balhimycin, Chloroorientiein, Chloropolysporin, Decaplanin, N-demethylvancomycin, Eremomycin, Galacardin, Helvecardin, Izupeptin, Kibdelin, LL-AM374, Mannopeptin, MM45289, MM47756, MM47761, MM49721, MM47766, MM55260, MM55266, MM55270, MM56597, MM56598, OA-7653, Orenticin, Parvodicin, Ristocetin, Ristomycin, Synmonicin, Teicoplanin, UK-68597, UK-69542, UK-72051, vancomycin, vancomycin B, their pharmaceutically acceptable salts and combinations thereof, for example as described in “Glycopeptides Classification, Occurrence, and Discovery,” by Rao R C and Crandall L W, in Drugs and the Pharmaceutical Sciences, Volume 63, Ramakrishnan N (ed.), Marcal Dekker, Inc., the entire disclosure of which is herein incorporated by reference. A “glycopeptide antibiotic” also includes the general class of glycopeptides disclosed above on which the sugar moiety is absent; i.e., the aglycone series of glycopeptides.
The liquid reservoir 12 in the illustrated example is a heated reservoir, for example, a Groen NE-30 vessel or a Groen NE-60 vessel. As used herein, an item which is “heated” is defined as an item which is structured to provide or retain heat, or a combination of both. Examples of heated items include items incorporating a heating element such as an electrical heating element or a conduit for heated liquid or gas to flow around the heated item, or as being sufficiently well insulated so that the temperature of the contents will remain within a desired range for a desired amount of time. The reservoir 12 includes a top cover 20 and a bottom valve 22. The reservoir 12 may further include a means for mixing or agitating liquid within the reservoir, thereby preserving the homogeneity of the liquid. Agitation is particularly useful if the liquid comprises a suspension. “Agitating” and “mixing” are used interchangeably herein.
A hose 24 leads from the bottom valve 22 of the liquid reservoir 12 to an inlet 13 of a pump 14. The illustrated example of the hose 24 is a BIOFLEX hose, available from Aflex Hose Ltd. Some example of the hose 24 and other hoses described herein, may be heated. Methods of heating the hose 24, and other hoses, include electric heating elements contained within the walls of the hose, or passageways defined within the walls of the hose to permit heated steam or fluid to flow therethrough. Examples of such heated hoses include embodiments of the above-mentioned BIOFLEX hose.
The illustrated example of the pump 14 is a Warren Rupp SANDPIPER double diaphragm ball valve pump. Other pumps may be used to transfer the liquid from the heated reservoir to the heated hopper. These pumps will fall into two categories: rotodynamic pumps and positive displacement pumps. Examples of each type include centrifugal, lobe, gear, peristaltic, cyclic, progressive cavity, and others. Some examples of the pump 14 may be heated, for example, by a blanket substantially surrounding the pump 14 and having heating elements therein. A second hose 26 leads from the outlet 15 of the pump 14 to the inlet 28 of the three-way valve 16. The hose 26 may be of similar construction to the hose 24.
The illustrated example of a three-way valve 16 is a pneumatic actuated valve available from Swagelok Company, located in Bolon, Ohio. Some examples of the valve 16 may be heated, for example, by a blanket having heating elements therein substantially surrounding the valve 16. A third hose 30, which in the illustrated example is also a BIOFLEX hose, leads from the first outlet 32 of the three-way valve 16 to the top 20 of the liquid reservoir 12.
The second outlet 34 of the three-way valve 16 leads to the hopper 18, which in the illustrated example feeds an encapsulator 36. Some examples of the hopper 16 are equipped with an agitator mechanism. A sensor 38 is structured to sense the level of liquid within the hopper 18, and is operatively connected to the three-way valve 16.
The heating of the liquid reservoir 12, hoses 24, 26, 30, and blankets covering the pump 14 and valve 16, may in some examples be controlled by proportional integral differential (PID) controllers that are operatively connected to temperature sensors. Such controllers are well-known in the art, the use of a PID controller facilitates maintaining a temperature between a desired minimum and maximum temperature which will vary depending on the liquid being used. For the example of a suspension of vancomycin HCl and propylene glycol or polyethylene glycol, the liquid may be maintained within a temperature range of about 60° C. to about 70° C., and more preferably may be about 68° C. The PID also permits a gradual reduction in the heat output of the various heat elements as a pre-determined temperature is approached, thereby avoiding overshooting the desired temperature. One example of a suitable PID controller is made by Red Lion.
In use, liquid within the liquid reservoir 12 is pumped by the pump 14 through the first hose 24, and second hose 26 into the inlet 28 of the three-way valve 16. If there is sufficient liquid within the hopper 18 to continue to feed the encapsulator 36, the liquid is directed by the valve 16 through the outlet 32 and hose 30 back into the liquid reservoir 12. The substantially continuous pumping of liquid through the pump 14 and valve 16, and then back into the reservoir 12, ensures that the liquid within the reservoir 12 remains mixed, thereby ensuring the homogeneity of the liquid.
When the level of liquid within the hopper 18 reaches a predetermined low level, the sensor 38 will actuate the three-way valve 16 so that liquid is now directed through the outlet 34 instead of the outlet 32, and into the hopper 18 until the liquid level within the hopper 18 reaches a predetermined high level. At this point, the sensor 38 will again actuate the three-way valve 16 to shut off the flow of liquid through the outlet 34, directing additional flow of liquid through the outlet 32.
Another embodiment of a liquid delivery system 40 is illustrated in
A liquid flow path extends from the liquid reservoir 42 to the hopper 48, and includes the hose 50 and valve 52. The hose 50 is similar to the hoses 24, 26, 30 in the system of
The liquid reservoir 42 is disposed above the hopper 48, so that when the valve 52 is open, liquid will flow from the liquid reservoir 42 to the hopper 48 due to gravity. The valve 52 is closed except when the sensor 54 senses that the level of liquid within the hopper 48 has dropped below a predetermined low level. At this point, the sensor 54 will actuate the valve 52, permitting liquid to flow from the liquid reservoir 42 into the hopper 48 until the level of liquid in the hopper 48 reaches a predetermined high level. Once the desired liquid level is reached within the hopper 48, the sensor 54 will again actuate the valve 52 to close the valve 52.
At the end of each fill cycle when transferring a suspension using the system 40, the hose 50 may be opened to the atmosphere or to a controlled gas such as to Nitrogen or Argon, ensuring that liquid within the hose 50 is substantially drained into the hopper 48, instead of remaining in the hose where the suspended solids may come out of suspension. The desired fill level of the hopper 48 may be adjusted downward prior to the last time the hopper 48 is filled during a production cycle to compensate for the additional fluid within the hose 50.
Referring to
A liquid flow path extends between the liquid reservoir 56 and the hopper 62. The liquid flow path in the illustrated example includes a hose 64 and a valve 66 structured to control the flow of product through the hose 64. The hose 64 is similar to the hoses 24, 26, 30 and 50 of the systems of
A method of automatically refilling a hopper for an encapsulator or other machine with liquid when the level of liquid within the hopper drops below a predetermined level is thus provided. The system minimizes the risk to personnel that would accompany manually filling the hopper. Some examples of the system ensure that the liquid is heated to a desired temperature as the liquid is being delivered to the hopper, or that the liquid remains within a desired temperature range during delivery of the liquid. Other examples of the system ensure that the liquid remains mixed (for example, to ensure homogeneity and to maintain the integrity of a suspension) as it is delivered to the hopper.
While specific embodiments of the invention has been described in detail, it will be appreciated by those skilled in the art that various modifications and alternatives to those details could be developed in light of the overall teachings of the disclosure. Accordingly, the particular arrangements disclosed are meant to be illustrative only and not limiting as to the scope of the invention which is to be given the full breadth of the appended claims and any and all equivalents thereof.
This application claims the benefit of U.S. provisional patent application No. 60/811,670, entitled “Liquid Delivery System,” and filed Jun. 7, 2006.
| Number | Date | Country | |
|---|---|---|---|
| 60811670 | Jun 2006 | US |
