BE893949A - PARENTAL DISTRIBUTION SYSTEM OF A USEFUL AGENT - Google Patents

Description

       

  "Parenteral delivery system of a beneficial agent"

  
Priority of four patent applications in the United States of America filed on July 31, 1981, under

  
n [deg.] 289.082, October 9, 1981, under n [deg.] 310.047, 19 oc-

  
  <EMI ID = 1.1>

  
under number [deg.] 325.206 on behalf of Felix Theeuwes and John Urquhart.

  
"Parenteral delivery system of a uti] -est agent

  
The present invention relates to a parenteral delivery system as well as to a formulation wafer containing a useful or beneficial agent. The invention also relates to a method for parenterally administering a useful agent using the parenteral delivery system comprising the agent formulation chamber, as well as to a method for adding an agent to a fluid.

  
Parenteral administration of medical fluids is an established clinical practice. Liquids are administered especially by the intravenous route, and this practice is widely used as an integral part of the daily treatment of patients in medicine and surgery. Liquids ha-

  
  <EMI ID = 2.1>

  
blood, dextrose solutions, electrolyte solutions, and saline solutions. Generally, fluids * are administered from an intravenous delivery system comprising a container suspended above the patient, with the fluid flowing through a hypodermic catheter and needle arrangement to to the patient.

  
The administration of liquids by the intravenous route is an interesting and important component which contributes to the optimal treatment of the patient; however, it does not offer a satisfactory method and means for administering a useful agent simultaneously with them. Currently, an agent of interest is administered intravenously by (1) temporarily separating the intravenous system and stopping the flow of liquid, and then administering the agent intravenously to the patient, this operation being followed by a reintroduction of the intravenous system to the patient; (2) the agent is added to the liquid in the container and is then transported by the flow

  
fluid to the patient; (3) the agent is added to a liquid in a separate container called a partial fill container which is connected to the primary intravenous tube through which the agent is brought by the flow of the liquid to the patient; (4) an agent is contained in a vial reported in

  
which introduces an intravenous fluid, the vial then being connected to the primary tube through which the drug is administered to the patient; or (5) the agent is administered by a pump which exerts a force on

  
a liquid containing the agent so as to administer the liquid containing the agent intravenously. Although these techniques are used, they have significant drawbacks. For example, administration of an agent by repeated introduction

  
needles cause unnecessary pain and trauma, they require separate connections to connect the primary IV line, which also complicates intravenous administration, the use of pumps can produce pressures which may vary at the delivery site and pressure can lead to thrombosis, the rate of delivery of the agent to the patient is often unknown since it is not a delivery of agent at a consistent rate.

  
  <EMI ID = 3.1>

  
these techniques often require prior formulation of the drug agent by the hospital pharmacist or nurse. In view of this, it immediately appears that there is a significant need in the field of parenteral therapy, in particular in the field of intravenous distribution, to carry out an elaboration process and a method of administration of a acceptable and reliable beneficial agent for a hospital at a rate controlled by parenteral delivery systems, particularly by intravenous delivery systems.

  
Therefore, a primary object of the present invention is to provide a parenteral delivery system for the administration of a beneficial agent.

  
at a controlled rate and an improved way to optimize the treatment of a human whose prognosis takes advantage of an intravenous distribution of a useful agent.

  
Another object of the invention is to provide a parenteral delivery system comprising a formulation chamber containing a useful agent

  
to admit the agent into a parenteral fluid so as to optimize the treatment of a patient during parenteral therapy.

  
Another object of the invention consists in providing a formulation chamber containing a dosage form of a useful agent, this chamber being suitable for use in a parenteral distribution system

  
to admit the beneficial agent at a rate controlled by the dosage form in a parenteral fluid admitted to

  
bedroom.

  
Another object of the invention is to provide a parenteral delivery system comprising an agent formulation chamber containing a useful agent and a rate control membrane for dispensing an agent formulation at a rate governed by the rate control membrane to a recipient.

  
Another object of the invention is to provide a parenteral delivery system comprising an agent formulation chamber containing a dosage form of an agent useful for the administration at a controlled rate of the useful agent in an admitted parenteral fluid. in the bedroom.

  
Another object of the invention is to provide a parenteral delivery system comprising an agent formulation chamber containing a device

  
agent delivery system for admitting an agent at a rate controlled by the delivery device into a parenteral fluid to optimize treatment of a patient during parenteral delivery.

  
Another object of the invention consists in providing an agent formulation chamber suitable for use with a parenteral delivery system,

  
  <EMI ID = 4.1>

  
agent for the admission of an agent at a rate essentially controlled by the device in a parent fluid <EMI ID = 5.1>

  
Another object of the invention is to provide a parenteral therapeutic system comprising

  
a container and a medicament formulation chamber which contains a device for dispensing a medicament at a rate governed by the device in a medical fluid which flows from the container into the chamber and then to a medicament receiver.

  
Yet another object of the invention is to provide a parenteral delivery system comprising

  
(1) a primary fluid passage, and (2) a secondary fluid passage comprising a formulation chamber containing (a) an agent delivery device for dispensing an agent into a medical fluid flowing in the chamber ., or (b) a useful agent, which agent in each case forms an agent solution in situ for administration to an animal, in particular to a human.

  
Another object of the invention is to provide a parenteral delivery system comprising (1) a primary fluid passage, comprising a formulation chamber containing (a) an agent delivery device for dispensing an agent into a medical fluid which flows into the chamber, or (b) a beneficial agent, and (2) a secondary fluid passage comprising a formulation chamber containing (a) an agent delivery device for dispensing an agent into a medical fluid that s flows into the room, or
(b) a useful agent, which agent in each case (a) or (b) forms in situ an agent solution for administration to an animal or a human being.

  
A parenteral delivery system and an agent formulation chamber are provided which formulation chamber is adapted for use with the parenteral system. The formulation chamber contains (a) a beneficial agent which formulates itself or mixes itself with a parenteral fluid entering the formulation chamber in situ and which is then infused into a biological recipient, or formulation chamber contains (b) a useful agent where the agent is initially present in agent delivery means, such as a device

  
agent delivery, or a dosage form to

  
controlled rate contained in the room, which stores a certain amount of a useful agent so as to carry out a prescribed program and provide a unique distribution. agent preprogrammed into the fluid entering the formulation chamber. The agent

  
useful when released by the distribution means is formulated in situ with the parenteral fluid which enters the formulation chamber. The delivery means in a preferred embodiment of the present invention release the beneficial agent at a controlled rate which is essentially independent of the flow rate of parenteral fluid entering the formulation chamber, and which is then infused to a recipient.

   The invention also relates to a parenteral delivery system for administering a fluid agent formulation, wherein the agent is formulated in situ with the fluid and wherein the parenteral delivery system comprises in combination: (a) a container for storing a pharmaceutically acceptable fluid which is also a pharmaceutically acceptable carrier for the agent; (b) a formulation chamber comprising a wall surrounding an opening and comprising a

  
surface inlet which allows communication with the container to allow the fluid to flow from the container into the formulation chamber, and a surface outlet

  
whereby the agent formulation leaves the room; (c) a useful agent .. a dosage form,

  
or a dispensing device in the formulation chamber; and (d) a conduit which communicates with the exit from the chamber and which extends to

  
catcher.

  
The invention also relates to a parenteral delivery system which comprises: (1) a passage

  
primary fluid consisting of a container containing medical fluid and a primary tube which communicates from the container to a common tube which leads to an infusion site in animals, and (2) a passage of fluid se-

  
  <EMI ID = 6.1>

  
in fluid communication with an agent formulation chamber which communicates with a secondary tube

  
and then with the passage of common fluid for infusion or introduction into the animal.

  
The invention also relates to the parenteral delivery system comprising: (1) a passage

  
primary fluid formed from a medical fluid container, a drip flow chamber, an agent formulation chamber, and a primary tube which communicates with the formulation chamber and a tube common which leads to an infusion site in an animal, and (2) a use of secondary fluid formed by a medical fluid container, a drip flow chamber, a formulation chamber agent, and a secondary tube which communicates with the chamber

  
  <EMI ID = 7.1>

  
infusion site or location.

  
Figure 1 illustrates a distribution system. <EMI ID = 8.1>

  
tion and this is generally designated by the reference numeral 10. The system comprises a container 11 made of a flexible plastic material,

  
or semi-rigid, preferably transparent, such as

  
polyvinyl chloride, or a polyolefin, and it contains a medical fluid 12 suitable for intravenous administration. The medical fluid 12 of container 11 will typically be a sterile solution, such as an aqueous dextrose solution, a dextrose solution in saline, an electrolyte solution or a saline solution. The medical fluid 12 is also a pharmaceutical carrier or carrier for intravenous administration, and it is a pharmaceutical carrier for the beneficial agent to be administered to a recipient. The container 11, in the illustrated embodiment, is not in communication with the atmosphere, the medical fluid contained therein is at atmospheric pressure, and the container collapses as it is filled with fluid 12.

   The container 11 is usually suitable for hanging the neck down on a hanging hook 13 by a button which connects to the container 11, or by a hole which is made in this container.

  
11. The container 11, at its end remote from its <EMI ID = 9.1>

  
suspension end, i.e. at its end

  
neck, has an administration opening 15, adapted to receive an administration set.

  
The administration assembly produced according to the present invention is used to dispense the fluid
12 and a beneficial agent admitted into the intravenous delivery system 10 to a patient. The administration device is sterile, pyrogen-free and must be discarded after use. The administration device includes

  
the elements described below, and it is connected to the opening 15 of the container 11. The opening 15 can be constituted by a diaphragm in the container 11, not shown

  
  <EMI ID = 10.1>

  
hollow connector 16. The connector 16 is adapted to receive the end 17 of the drip flow chamber 18, this end 17 being well fitted on the connector 16. The drip flow chamber 18 is used to trap of air and allow the adjustment of the flow rate of the fluid 12 from the container 11 when the flow is done drop by drop. An outlet 19 of the drop-by-drop flow chamber 18 is connected to a first tube segment 20 which fits in the outlet 19. An adjustable clamp 21 of the roller or screw type on the tube 20 thins the internal diameter of the tube 20 for regulating the flow in cooperation with the drip flow observation chamber 18. A second segment of tube 20 is connected to the inlet 23 of an agent formulation chamber 22.

   A third tube segment 20 is connected to the outlet 26 of the formulation chamber 22 and to an adapter-needle assembly 27 which is introduced into a vein and sometimes into an artery of a warm-blooded animal.

  
The agent formulation chamber 22 is a particular element of the intravenous delivery system both as a chamber alone and in combination with the system. The formulation chamber 22 is dimensioned and adapted for use in intravenous systems, it is autonomous, self-priming, self-actuated, self-composition, and can be manufactured at low manufacturing cost. The formulation chamber 22 contains an agent of interest which can be administered intravenously, and the use of the formulation chamber 22 with the agent which it contains does not require any reconstitution or any mixture before use. The agent formulation chamber 22 is a disposable chamber, of low weight comprising a wall 24 which surrounds and which delimits an interior space or orifice 25.

   Bedroom
22 has an inlet 23 adapted and sized to be placed in an intravenous delivery system, and it has an outlet 26 also suitable for placing the chamber in the system. The inlet 23 and the outlet 26 are made to receive the tube 20. The chamber 22 is made of glass, of a plastic material

  
or a similar material, and as shown, it is made of a transparent material to illustrate its structure and the agent it contains. The agent in chamber 22 can be in any pharmaceutical package which forms an agent formulation with the fluid entering the chamber. Examples

  
of pharmaceutically acceptable forms are the solid, crystalline, microcrystalline, particulate, lozenge, granular, pulverulent, tablet, spray-dried, lyophilized, compressed forms which undergo disintegration and dissolution in the presence of a parenteral fluid, in particular of an intravenous fluid, such as compressed particles, compressed powders, compressed granules, friable layers of agent, in a delivery device which releases the agent at a rate controlled by the device in the fluid entering the formulation chamber 22, in the form of a dose, etc.

   The agent formulation chamber 22 will generally store a certain quantity of useful agent in a dispensing device, in a dosage form, in a pharmaceutical form, etc., so as to carry out a prescribed therapeutic or useful program, , i.e. a certain amount of agent

  
for the single, pre-programmed delivery of a therapeutically or usefully effective amount to produce a therapeutic or useful result. The agent formulation chamber 22 will generally

  
  <EMI ID = 11.1>

  
more, and it can contain about 5 mg to 20 g of agent or more in different dispensing devices and in different pharmaceutical forms.

  
The term "useful agent", as used in the context of the present invention, generally means any substance which produces a therapeutic or useful result, such as a drug, a carbohydrate, an electrolyte and / or a similar material. The term "fluid" or "liquid" means a fluid or liquid which can be administered parenterally including the intravenous route, this term comprising pharmaceutically acceptable fluids which are also a pharmaceutically acceptable carrier for an agent, such as water , isotonic saline solutions, Ringer's lactate, etc.

   The term "formulation" and the expression "agent formulation" as used in the context of the present invention generally indicate that the useful agent is formulated, mixed, added, dissolved, in particular. suspension and / or supported, etc., in or by the fluid in a physico-chemical form acceptable for parenteral administration, including intravenous administration. According to another embodiment of the invention, the formulation chamber 22 can simultaneously act as a drip flow chamber while containing a device or an agent. In this embodiment,

  
the formulation chamber-drip chamber is used to achieve a desired fluid drop rate. For example, the formulation chamber-drip chamber may have a fast drop speed for adults, or it may have a slower drop speed for use in pediatrics. The drip chamber formulation chamber may have different inputs sized to control the rate of the drip flow, or the drip flow may be controlled by an adjusting clamp on the tube supplying the fluid. The drip chamber formulation chamber can deliver, for example from 2 to 75 drops per ml over a period ranging from 1 minute to 1 hour.

   More preferably, the therapist can adjust the flow rate between 1 and
20 drops per minute, or as needed by the patient. Another description relating to the * formulation chamber
22 is given below.

  
FIG. 2 illustrates another operational parenteral therapeutic system of the present invention. <EMI ID = 12.1>

  
digital reference 10. The system 10 is supported in the dispensing position by a support 30. The system

  
10 is a system of the type in communication with the atmosphere, which requires air to function. The system 10 comprises a container 31 made of glass or of a transparent, rigid plastic material, suitably sealed by means of a rubber stopper, not shown, which is held in the container 31 by means of a flange ring closure

  
32. The container 31 contains a fluid 33 preferably designed for intravenous administration. Air enters the system 10 through the air inlet 34 formed in the inlet closure 55 of the drip chamber 36. A point 37 which is hollow pierces the rubber closure of the container 31 and serves as a conduit for letting air pass from the air inlet 34 into the container 31 and as a conduit for letting the fluid 33 pass from the container 31 into the drip chamber 36. One end 38 of the tip 37 is shown in the container 31, the other end of the tip 38, not shown, entering the drip chamber 36 to bring the fluid 33 from the container 31 into the drip chamber 36 .

   The drip flow chamber 36 is of tubular, hollow, traditional design formed by a wall surrounding an internal fluid reception orifice and is connected to an agent formulation chamber 39 by means of a first tube section 40 introduced into its outlet end
41 of the drip flow chamber 36, and it is also introduced into the end of the formulation chamber 42 adapted to receive the tube 40. The other end 43 of the formulation chamber 39 is adapted to receive a second section of tube 44.

  
The formulation chamber 39 is made of glass or

  
plastic, and is preferably transparent. The formulation chamber 39 may have any shape suitable for use in a parenteral delivery system incorporating intravenous delivery systems, and is preferably rounded and its length is greater than

  
its width. The ends 42 and 43 easily adapt to the wall of the chamber 39 to form a leak-tight, airtight closure, in order to receive a distribution system which releases an agent so as to form a solution. 'agent

  
in situ, in the chamber 39 with the fluid 33 entering the chamber 39 from the container 31 by mixing or dissolving therein. The tube 44 brings the solution containing the useful agent from the chamber 39 to the needle 45 for administration to a host. An adjustment clamp 46 is provided on the tube 40 to thin the inside diameter of the tube 40 so as to regulate the flow of the fluid 33 through the system 10.

  
FIG. 3 illustrates another parenteral system, mainly intravenous, produced according to the present invention. The system 10 comprises in combination a container 48 which is a reservoir of a pharmaceutically acceptable fluid and it comprises an aeration tube 49 which allows air to enter the container when the medical fluid is infused or introduced into a patient. The container 48 is closed by means of a stopper, not shown, and it has

  
an opening for the ventilation tube 49. The container 48 is connected by means of an adapter
50 in the form of a hollow point having no ventilation in the parenteral system for sending the medical fluid from the container 48 through the system 10 to a patient. The tip 50 is connected to a first section of tube 51 which enters a drip flow chamber 52. The drip flow chamber 52 is, as described above, preferably made of a material which makes it possible to see through, such as glass or plastic so as to be able to count with the naked eye a desirable number of drops which pass through this chamber for a unit of time. A second section of tube connects the drip flow chamber 52 to a formulation chamber 53.

   The second tube section 51 passes through a clamp 54 used to regulate the flow. The formulation chamber 53 includes a wall 55 which surrounds the interior space 56. The chamber 55 contains in the space 56 a unit dosage quantity of agent 57, as represented by dotted lines, so as to carry out a program useful, or it may contain a dispensing device, or any other pharmaceutical form. Agent 57 is present in a pharmaceutically acceptable form which may undergo dissolution, or it may disintegrate into smaller pieces and dissolve in the presence of the liquid in

  
chamber 55 so as to form an agent solution. Chamber 55 can optionally contain a filter element to form a sterile fluid by separation of the particulate matter and / or bacteria

  
of the fluid, this element not disturbing the flow of the fluid passing through the chamber. Dispensing from this system can be controlled, for example, by the rate of dissolution as governed by the di-. agent particle size and solubility

  
of agent in the fluid, by the rate of release from a dispensing device, etc. Chamber 55 has one end 58 for receiving an incoming tube
51 and the medical fluid coming from the container 48, and it has an end 59 for receiving the outgoing tube 51. The tube 51 brings the agent solution from the chamber 53 comprising a usefully effective quantity of agent 57 via needle 60 to a patient to produce the expected useful effect.

  
FIG. 4 represents a parenteral distribution system produced according to the present invention and is generally designated by the reference numeral 10. The system 10 comprises a primary container 62 made of a flexible or semi-rigid plastic material, preferably transparent , such as a non-toxic polyolefin, polyvinyl chloride, etc. The primary container 62 is a parenteral container of large volume and it contains a medical fluid 63 suitable for parenteral, intravenous therapy.

  
or any other therapy. The medical liquid 63 in the container 62 will typically be a sterile solution, such as an aqueous dextrose solution, an electrolyte or a saline solution. The container 62, in the illustrated embodiment, is

  
without communication with the atmosphere, the medical fluid is at atmospheric pressure, and the container collapses as it fills with medical fluid 63. The container 62 is usually adapted

  
to hang the neck down on a hanging hook 64 by a button that connects to the container

  
62, or else through a hole 65 which is made in the container 62. The container 62, at its remote end

  
from its suspension end, that is to say at its neck end, has an administration opening adapted to receive a primary fluid path.

  
The primary path is used to deliver the medical fluid 62 through the parenteral therapeutic system 10 to a patient. The primary route or passage is sterile, pyrogen-free and must be discarded after use. The primary passage comprises the elements described below, and it is connected to the opening 66 of the container 62. The opening 66 may be constituted by

  
a diaphragm in the container 62, not shown, or else the opening 66 may consist of an adapter intended to receive a hollow connector 67. The connector 67 is made so as to receive the end 68 of a flow chamber drip 69. The drip flow chamber 69 is used to trap air and it also allows, in association with the regulating clamp 70, the adjustment of the flow of medical fluid 63 coming from the container 62 when the flow is done drop by drop. An outlet 71 from the drip flow chamber 69 is connected to one end of a primary tube 72 which passes through a regulating clamp 70 intended to thin its internal diameter so as to regulate the flow in association with the d chamber. 'flow

  
drip, observation 69. The other end of the primary tube 72 connects to a valve 73, from which a common tube 74 connects from the valve 73 to an adapter-needle assembly 75 which is introduced, for example, in the vein of a warm-blooded animal.

  
The system 10 further comprises a secondary fluid passage, this secondary passage being formed of a secondary container 76 or of a mini-bag made of a flexible or semi-rigid plastic material, preferably transparent, such as a non-toxic polyolefin. , polyvinyl chloride, or the like. The secondary container 76 is a parenteral container of small volume and it contains a medical fluid 78 suitable for parenteral, intravenous therapy or for any other therapy. Medical fluid
78 is a pharmaceutical vehicle for parenteral administration, i.e. it is a pharmaceutical carrier for a drug which is to be administered

  
to a receiver. The container 76, in the illustrated embodiment, is unventilated, the medical fluid
78 is at atmospheric pressure, and the container is crushed or collapsed as it is filled with medical fluid 78. The container 76 is adapted to be suspended from the neck down on a hook. suspended. sion 64 by a button which connects to the container 76, or by a hole 79 which is made in the container 76.

  
The container 76, at its end remote from its suspension end, that is to say at its neck end, has a suitable administration opening

  
to receive a secondary fluid passage.

  
The secondary fluid passage provided by the present invention is used to dispense the medical fluid 78 into which a drug is added, to a patient. The passage or secondary route is sterile, pyrogen-free and must be discarded after use. The secondary passage includes the elements described below, and it

  
connects to the opening 80 of the container 76.

  
The opening 80 may consist of a diaphragm in the container 76, not shown, or

  
well the opening 80 can be an adapter intended to receive a hollow connector 81. The connector 81 is designed to receive an end 82 of the drip flow chamber 83. The drip flow chamber 83 is used to trap of

  
air and it also allows, in association with the regulating clamp 84, the adjustment of the flow rate of the medical fluid 78 coming from the container 76 when the flow is done drop by drop. An exit 85 from the

  
drip flow chamber 83 is connected to

  
one end of a segment of secondary tube 86 passing through the regulating clamp 84 to thin its internal diameter so as to regulate the flow in association with the drop-by-drop, observation flow chamber 83. The other end of secondary tube 86 is connected to an agent formulation chamber 87. The regulating clamp 84 is used to regulate the flow of fluid in the agent formulation chamber 87.

  
The formulation chamber 87 is made of glass or

  
in a plastic material, and it is preferably transparent. The formulation chamber 87 may have any shape suitable for use in a parenteral therapeutic system, it is preferably rounded and its length exceeds its width. Secondary tube end 86 easily adapts

  
with the end plug 89 of the chamber 87. The end of the secondary tube can be fitted in the plug 89 or it can slide on a tube receiving member of the plug or cap 89 so as to form a chamber impermeable to leaks, airtight to contain at least one beneficial agent, or a dispensing device. The chamber 87 is optionally provided with a membrane controlling the rate of release, not shown, for example a microporous membrane or of a similar type, which regulates the rate of release of agent solution coming from the chamber

  
87. The membrane controlling the rate of release can rest on a sintered glass support made in one piece with the chamber, the membrane can optionally be adhesive-sealed to the interior wall of chamber 87, be welded to this one,

  
be supported by the wall of the chamber pinched inwards, arranged on a rim in the chamber, or it can be supported or be fixed in an appropriate manner to the end plug 90 placed in the chamber 87. A segment secondary tube 91 brings the agent solution from the chamber 87 to the valve 73. A regulating clamp 92 is optionally provided on the tube 91 so as to facilitate adjustment of the flow rate of the agent solution coming from the formulation chamber . The regulating clamp 92 can be used alone, in cooperation with the clamp 84, in cooperation with the valve 73, and in cooperation with the valve 73 to regulate both the flow of the fluid and the flow of the agent solution by the secondary passage.

   The valve 73, in a preferred embodiment of the invention, is a three position valve. The agent solution is sent from the valve 73 through the common tube 74 to the needle assembly 75 for administration in a container. That is to say that the fluid can be brought in from the primary passage, from the secondary passage, or else from the two passages by regulating the valve for the flow to a receiver. For example, the fluid can be sent through the tube 72, the valve 73, the tube 74

  
and the needle 75, or from the tube 91, through the valve 73, the tube 74 and the needle 75, or the valve can be adjusted to send the fluid from these two passages.

  
FIG. 5 represents a parenteral distribution system produced according to the present invention and generally designated by the reference numeral 10. The system 10 of FIG. 5 illustrates a system of the ventilated type which requires air to function. System 10 includes a glass container
94, suitably sealed with a rubber stopper and contains a medical fluid acceptable for parenteral administration, including for intravenous administration. The container 94 is supported in the dispensing position by a support
95, and the air enters the container 94 via the filter

  
air 96 connected to container 94 via

  
of a point 97 which is hollow and which pierces the rubber closure of the container 94. The other end of the point 97, not shown, enters a

  
drip flow chamber 98 and it sends the medical fluid from container 94 into the drip flow chamber 98. The drip flow chamber 98 is connected to a primary fluid passage formed by a tube of medical quality which sends the medical fluid to a needle 100. A roller clamp 101 is provided on the fluid passage 99 to reduce the internal diameter of the primary passage
99 so as to regulate the flow of fluid through it. The system 10 of FIG. 5 also includes a secondary fluid passage 102 which connects a common passage 103 to a bypass fitting 104.

  
The branch fitting 104 can be made in the form of a connection tube of type Y so as to receive the primary passage 99, the secondary passage

  
102 and the common passage 103.

  
The secondary passage includes a container
105 which is a mini-container or a glass mini-bottle, and it is suitably sealed by means of a rubber stopper, not shown, and it contains a medical fluid acceptable for parenteral administration, including for intravenous administration. The container 105 is supported in the dispensing position by the support 95, and air enters the container 105 through a filter 106 connected to the container 105 by means of a point 107, which point is hollow and pierces the closure. rubber container
105. The other end of the tip 97, not shown, enters a drip flow chamber 108 and it brings the medical fluid from the container

  
105 in the drip chamber 108.

  
The drip flow chamber 108 is connected

  
to a secondary fluid passage 102 consisting of a medical quality tube which sends the medical fluid carrying a useful agent to the needle 100.

  
A roller clamp 109 is provided on the secondary fluid passage 102 to reduce the internal diameter of the secondary passage 102 so as to regulate the flow of the fluid via the secondary passage in the agent formulation chamber 110. agent formulation chamber 110 is sized and suitable for use in the parenteral delivery system 10. The agent formulation chamber is self-contained, self-priming, self-actuated and can be manufactured at low manufacturing cost . The formulation chamber 110 is light in weight and is

  
to throw away after use and it includes a wall 111

  
that surrounds and defines an orifice or interior space
112. The formulation chamber 110 has an inlet
113 intended to receive the secondary passage 102 and has an outlet 114 also suitable for placing the chamber 110 in the secondary passage 102. The chamber
110 is made of glass, plastic or the like, and as shown, it is made of a transparent material to see its structure. The chamber 110 can contain a useful agent or an agent distribution device. An agent formulation formed in the chamber 110 leaves the chamber 110 through the secondary passage 102, joins the fluid coming from the passage 99 to the connector 104 and then passes into the common passage 103 for introduction or infusion in a recipient.

  
Figure 6 illustrates another parenteral system 10 of the present invention. The system 10 comprises a primary passage 110 and a secondary passage
119 supported in the fluid and agent delivery position above a patient by a loop support
120. The primary passage 118 comprises in combination a container 121 which is a pharmaceutically acceptable liquid reservoir 122 and which comprises an internal ventilation tube 123 which allows air to enter the container 121 when the medical fluid leaves the container 121 and is infused to a patient. The recipient
121 is a large parenteral container containing a sterile fluid used for the modification and maintenance of physiological functions in a recipient. The container 121 is closed by means of a plug 124 held in position by a crimped rim 125.

   The ventilation tube 123 extends through the plug
124 for the admission of air into the container 121. The container 121 is in communication for a fluid with the drip flow chamber 126 via its hollow pointed end 127 which pierces the plug 124. The Drip chamber 126 is, as previously described, used to visually count the number of drops 128 of medical fluid 122 which passes through drip chamber 126 over a unit of time. Drip chamber 126 has an enclosed space to hold the medical fluid and is closed at its end by a pair of capsules
129 and 130 which slide easily on the tubular wall 131 so as to form the aforementioned sterile fluid chamber.

   The fluid chamber is made of a material through which we can see, such as glass or a transparent plastic to see the drops. The medical fluid leaves the flow chamber drop by drop through a first section of tube 132 which brings the medical fluid into a formulation chamber 133. The formulation chamber 133 comprises a wall 134 which surrounds an internal space
135 and it is closed at its ends 136 and 137 by closures which adapt to the aforementioned chamber wall. The tube 132 enters the closure 136 to establish a fluid communication between the formulation chamber and the drip flow chamber,

  
  <EMI ID = 13.1>

  
this flow 139 transports the fluid to a two-position valve 140. The fluid passes through the valve
140 in the common tube 141 and a needle assembly 142 to a receiver.

  
The secondary passage 119 is formed by a container 143 which is a device for storing a pharmaceutically acceptable liquid 144. The container
143 has an internal ventilation tube 145 for letting air enter it. The container 143 is closed by a stopper held in place by a rim 147. The container 143 is a mini-container, or a mini-bottle and it contains approximately 100 to 500 ml of liquid which is used for continuous transport of medicament, or else for intermittent transport of medication to a patient. Container 143 is connected

  
to a drip flow chamber 143 via an adapter 149 in the form of a hollow point intended to send the medical liquid from the container
143 through the secondary passage to a patient. The drip flow chamber 148 is designed to count the number of drops 150 that pass through the aforementioned drip flow chamber 148 during a unit time. The medical fluid leaves the flow chamber drop by drop through a first section of tube 151 which leads to a formulation chamber 152. The agent formulation chamber 152 is, as described above, constituted by a wall formed by a fluid impermeable material which surrounds an interior space so as to contain a certain dosage amount of a beneficial agent, or a dispensing device.

   Chamber 152 has a known volume and preferably has a volumetric scale to indicate the volume of fluid therein. The chamber 152 has an end 153 adapted to receive the incoming tube 151 and an end 154 adapted to receive the outgoing tube 155. The tube 155 passes through a clamp 156 and can be used as an all-or-nothing regulator, or as volume flow regulator to regulate the flow of fluid through the secondary passage. The tube 155 brings the fluid carrying the useful agent from the chamber 153 to the valve 140, and from there, via the common fluid communication tube 141 to a needle assembly 142 and to a living recipient.

  
In operation, the parenteral delivery system 10 of Figure 6 is used in the same way as the parenteral delivery system 10 of Figure 5. That is, one can use the system 10 of Figure 6 (1) for administering a previously selected medical fluid containing a previously selected beneficial agent by opening the forceps
139, by closing the regulating clamp 156 and by positioning the valve 140 so as to let the fluid flow from the tube 138 into the tube 149, (2) for the administration of a medical fluid chosen previously different containing a useful agent chosen beforehand different by opening the regulating clamp 156, by closing the regulating clamp 139 and by positioning the <EMI ID = 14.1>

  
tube 155 in tube 141, and (3) for the administration, at a selected dosing time, of a given volume of fluid containing a known quantity of agent (a) by letting the fluid flow through the primary passage or

  
  <EMI ID = 15.1>

  
141 in the closed position for the primary passage or the secondary passage, (b) by letting a known volume of fluid enter each formulation chamber, this volume being determined by reading the meniscus relative to

  
) port on a volumetric scale on the chamber, (c) by formulating the agent formulation in the chamber by dissolving a given quantity of agent present in the chamber, or distributed by a device in the latter , in the known volume of fluid, which quantity of agent soluble in the fluid dissolves as a function

  
time, and (d) metering a recipient with the agent solution whenever desirable by positioning valve 141 so as to allow the solution to flow from the desired formulation chamber. This is how the invention makes it possible to distribute

  
the same fluid and different drugs, or

  
different fluids and different drugs to

  
a patient by previously selecting the fluid and

  
the drug for the primary or secondary passage. The invention also provides modes for continuing, modifying, or discontinuing drug therapy.

  
Figure 7 shows a parenteral system
10 made in accordance with the present invention. The parenteral system 10 is a gravity flow system intended for the administration of two medical fluids and two useful agents at independent rates, or cooperating via two separate distribution passages, namely a primary passage and a secondary passage. The primary passage 158 comprises a container 159 which contains a primary medical liquid 160 to be administered to a patient over an extended period of time and it is supported in the dispensing position by a suspension hook 161. The primary fluid supply container 159 is made of glass or a non-toxic, transparent plastic and is sealed under sterile conditions.

   The container 159 is sealed by means of a rubber stopper 162 held therein by a closure

  
of the annular retaining rim type 163.

  
The primary container 159 is in fluid communication with a drip flow chamber 164. The drip flow chamber

  
164 is in fluid communication with the container

  
159 by means of a hollow point 165 which passes through the plug 162 in the container 159.

  
The drip flow chamber 164 is an air type, ordinary drip flow chamber well known in medical practice. Basically the drip chamber
164 is made up of two parts, a conical envelope

  
166 intended to receive the fluid, which is provided with a capsule 167 at its entry and which terminates in an orifice

  
outlet 168. The drip flow chamber
164 allows air to enter the parenteral system through the air inlet 161 formed in one piece with the encapsulated inlet 167. The rate of drip 169 of the fluid flowing from the container 159 is adjusted by a clamp 170 provided downstream on the primary passage. A first section of medical grade tube 171 introduced into outlet 168 establishes communication for a fluid between the drip flow chamber 164 and the inlet 171 of the chamber.

  
  <EMI ID = 16.1>

  
The agent formulation chamber 172 is sized and adapted for use in the parenteral delivery system 10. The agent formulation chamber 172 is self-contained, self-priming, self-actuated and can be manufactured at low cost.

  
The formulation chamber is of a light weight, it is to be discarded after use, and it is carried out in

  
a preferred embodiment of the present invention in a transparent, clear material, such as glass or a plastic material. The formulation chamber
172 comprises a wall 173 which surrounds and which forms an interior space 174, and it comprises an inlet closure 175 which receives the tube 171, and an outlet closure 176 adapted to receive the tube 177. The tube 177 passes through the clamp 170 designed to reduce

  
the internal diameter of the tube 177, so as to regulate or stop the flow of fluid through the primary passage. The tube 177 enters a connector 178 produced in the form of a connection tube of the type

  
  <EMI ID = 17.1>

  
177 and a common tube 179 which leads to an injection member 180 for administering the agent formulation to a patient.

  
The secondary passage 181 comprises a container 182 which is a mini-container or a mini-bottle made of glass or of a plastic material, suitably sealed by means of a stopper

  
of rubber 183 held in container 182 by

  
a closing bead 184. The container 182 is supported in the dispensing position by the support

  
161 and it contains a medical fluid 185 acceptable to

  
both for parenteral administration, in particular intravenous administration and as a transport medium for a useful agent. Air enters the container 182 through a forced air inlet 186 in one piece with the tip 187, which point is hollow and pierces the rubber closure 183 of the container
182. The other end 188 of the tip 187 passes through the closing inlet 189 of a drip flow chamber 190 to bring the drops of medical fluid 191 from the container into the drip flow chamber . The drip flow chamber 190 is in communication for a fluid via a tube 192 with the formulation chamber 193.

   The agent formulation chamber 193 is designed as the formulation chamber 172 described in the primary passage, and this description is included and applicable for the chamber 193. The formulation chamber 193 is connected to a secondary tube
194, made of a medically acceptable material, which passes through a V-clamp 195 so as to regulate or stop the flow of agent formulation through the secondary passage. The tube 194 enters the fitting 178 to flow into the common passage 179 for infusion via a

  
  <EMI ID = 18.1>

  
The agent in the formulation chambers 172 and 193 can be in any pharmaceutical state, present as an agent per se, or in a device, which device forms a fluid formulation comprising an agent and a medical fluid which enters the chambers 172 and 1.93 and which does not require any reconstitution or mixing before use. The flow of medical fluid in the formulation chamber
172 or 193 can be started, stopped, adjusted or interrupted by clamp 170 or clamp 195, used alone or together, which allow the tube 177 or tube 194 to remain open, closed or partially obstruct the passage of the fluid to the across tube 177 or 194, and correspondingly the flow

  
agent solution can also be adjusted from room 172 or 193.

  
In operation, the parenteral delivery system lo as illustrated in FIG. 7 can be used by a doctor, or a practitioner in a hospital environment as follows: (1) to administer a medical fluid containing a useful agent through the primary passage by adjusting the regulating clamp 170 to open and closing the regulating clamp 194 to prevent the flow of fluid in

  
the secondary passage, thereby ensuring flow through the primary passage and into the needle 180 serving

  
piercing the skin, (2) to administer a medical fluid containing a useful agent through the secondary passage by adjusting the regulating clamp 195 to open and closing the regulating clamp 170 to prevent the flow of fluid in the primary passage,

  
thus ensuring the flow through the secondary passage and into the needle 180 used to pierce the skin, and

  
(3) to administer a certain amount of agent into a known volume of fluid from the two passages

  
by regulating the flow of fluid by means of the regulating clamps 170 and 195, which fluid

  
in both cases mixes in the form of a common fluid at the location of the connector 178 for its subsequent administration to a patient. The operations provided for by these embodiments of the invention make it possible to carry out continuous and interrupted administration of two different agents in two different fluids passing through two different passages, and administration of two different agents in different fluids during the same agent administration time interval.

  
Figures 8 to 25 show structural embodiments. formulation chambers

  
which can be used in the intravenous distribution system of Figures 1 to 7. Figure 8 shows a formulation chamber 197 which is of light weight, to be discarded after use and which is indicated for use in patients requiring parenteral administration of a fluid containing a beneficial agent. In FIG. 8, the chamber 197 comprises a body 198 of tubular shape and it comprises a pair of capsules
199 and 200 so as to form a closed chamber for containing the fluid and the agent.

   The capsules 199 and 200 fit onto the body 198 and they are preferably made of self-sealing rubber through which a needle or a hollow point can be introduced, or they can be made of rubber with a hole drilled beforehand covered with a latex disc through which communication can be carried out with the internal chamber 197. The formulation chamber 197 can preferably be hermetically sealed, is moisture-proof, impermeable to microorganisms, and permeable to ionizing rays to allow sterilization. FIG. 9 represents a formulation chamber 201 with a part eliminated to represent the interior of the hollow body of the chamber. In FIG. 9, the chamber 201 comprises a wall 202 with a removed part and ends 203 and 204. These ends

  
closure 203 and 204 fit onto the body of the formulation chamber 201, these ends 203 and 204 comprising a hollow receiving member 205 and 206 intended to receive a tube which can slide in or slide on the receiving member. The formulation chamber 201 contains a useful agent 207 which is soluble in parenteral fluids, such as in an intravenously acceptable fluid, and a film 208 formed of a material for controlling the flow of the fluid and l room officer 201.

  
The film 208 according to a preferred embodiment is formed of a polymer making it possible to control the

  
release rate of the agent, such as a microporous polymer such as a polycarbonate, a semi-permeable polymer such as cellulose acetate, or a diffusion polymer such as a copolymer of ethylene and acetate

  
vinyl. The polymer film produced according to the invention is used in a preferred embodiment of the invention to regulate the rate of release of the solution containing the agent from the chamber.
201, that is to say the release of the agent and of the flow of fluid by the chamber 201. The chamber
201 is shown with a film at its exit, and it may possibly include a film at its entry.

  
FIG. 10 represents a formulation chamber 209, in open view, comprising an agent 210 in particulate form, a polymer film allowing the control of the release rate 211, such as cellulose acetate or a similar material, and a thread. -be 212. The filter 212 is an ordinary filter with

  
a pore size of 0.1 micron to 5 microns, and more preferably 0.22 micron or 0.45 micron, to separate bacteria and unwanted material from the flowing solution, thereby facilitating to maintain a sterile solution.

  
FIG. 11 represents a formulation chamber 213 comprising a walled body 214 of tubular shape and it comprises a pair of capsules 215 and
216 so as to form a closed chamber containing a fluid and a system. of distribution. Capsules
215 and 216 fit on the chamber 213 and they can comprise a tubular extension 217 and 218 produced in a single piece with these to receive an incoming tube. The hollow tubular members 217 and 218 are preferably rounded to receive a tube which slides in, or which slides on the member. This system

  
dispenser shown in formulation chamber 213 includes a multitude of tiny pills

  
delayed dosing 219 (chronules) for the controlled distribution of an agent, in particular a medicament, into a fluid entering the chamber 213. The tiny pills are shown in detail, in the form of open pills 220, and they comprise a core of medicament 221 surrounded by a wall 222 made of a material making it possible to control the rate

  
of release. The tiny delayed-dose pills 219 have a high membrane surface area to achieve high agent release rates so as to form an agent solution. The total number of tiny pills 219 in formulation chamber 213 may vary as an additional means of adjusting

  
the amount of agent made available to form an agent solution. The materials used to form

  
the wall 222 can be used among the materials which release the drug 221 by different physicochemical mechanisms. These mechanisms incorporate the mechanisms of erosion, diffusion and osmosis. The wall 222 when it releases the drug by osmosis, releases the drug by bursting. The drug 221

  
in this embodiment is, present under the

  
form of an osmotic solute, such as an acceptable salt

  
therapeutically, and it has an osmotic pressure gradient across wall 222 relative to an external fluid. The membrane materials used to form the wall 222 are materials permeable to the passage of an external fluid and practically impermeable to the passage of the drug. Characteristic materials are chosen from the group comprising cellulose acylate, cellulose diacylate, cellulose triacylate, cellulose acetate, cellulose triacetate, etc. The osmotic wall can be applied around the medicament in different thicknesses by means of coating with a bowl, coating with a spray bowl, coating with pneumatic suspension by Wurster fluid, etc.

   The wall is formed using organic solvents, such as methylene methanol chloride, methylene acetone chloride, methanolacetone, ethylene acetone dichloride, etc. Osmotic wall generating materials, processes for forming the wall, and osmotic bursting processes are described in US Pat. Nos. 2,799,241, 3,952,741, 4,014,334 and
4,016,880.

  
The wall 222 of the tiny pills 219 can, according to another embodiment, be made of a material intended to control the rate of release of the drug. That is, the drug 221 dissolves in the wall or in the pores of the wall and passes through the wall or through these pores at a rate controlled by diffusion as a function of time. Examples of materials useful for forming a diffusion wall or a wall comprising pores are the copolymers of ethylene and vinyl acetate, ethyl cellulose,

  
polyethylene, crosslinked polyvinyl pyrrolidone,

  
copolymers of vinylidene chloride-acrylonitrile, polypropylene, silicone, etc. The wall can be applied by the techniques described above, and suitable materials for forming the wall 81 are described in the United States patents

  
n [deg.] 3,938,515, n [deg.] 3,948,262 and n [deg.] 4,014,335.

  
The wall 222 of the tiny pills 219

  
can be made of a bioerodible material which erodes biologically at a controlled rate and releases the drug 221 into the fluid of the chamber 213. Bioerodible materials which are useful for forming the wall 222 are polycarboxylic acid, polyesters, polyamides, polyimides, polylactic acid, polyglycolic acid, polyorthoesters

  
and polycarbonates. These polymers and processes

  
to form the wall 222 are described in the patents of the United States of America n [deg.] 3,811,444, 3,867,519,
3,888,975, 3,971,367, 3,993,057 and 4,138,344. The amount of medicine in a tiny delayed-dose pill is generally about
10 mg to 20 mg, and the number of tiny pills in a chamber is in the range of 10 to 1000, preferably 50 to 150. The tiny pills comprising the wall and the inner core of the drug have a diameter of at least minus 10 microns, and in a preferred embodiment of the invention, they have a diameter

  
at least 2,000 will deny it. Tiny pills can have one or more layers of wall-building matter. Room 213 is optionally provided with a support 223 for tiny pills.

  
The support 223 can consist of a film

  
having release rate control properties

  
and be made of a polymer which releases the drug from the chamber 213, the support 213 can also be a microporous polymer membrane, a sintered glass support, a perforated grid, and / or etc.

  
FIG. 12 represents a formulation chamber 224 illustrating a similar chamber comprising a wall 226 surrounding an orifice 222 comprising an inlet 228 and an outlet 229. The chamber 224 contains a series of tiny capsules 230, these capsules also being presented opened by the reference 231. The capsules 230 include a wall
232-enveloping a mass of liquid drug 233. The tiny capsules can be produced by means of a coacervation technique which essentially consists of forming three immiscible phases, a phase of preparation of the liquid, a phase of material forming

  
core and a coating phase..The coating phase <EMI ID = 19.1>

  
forming a core and is usually made rigid by

  
thermal, crosslinking or desolvation techniques to form tiny microcapsules. The capsules prepared by this technique have an average particle size ranging from several tenths of a micron up to 5000 microns, and in some embodiments, tiny capsules of larger dimensions can be used. However,

  
the particle size is not critical in the context of the present invention. Suitable techniques for the preparation of tiny microcapsules are reported by Bungenberg de Jong and Kass, Biochem.Z., Vol. 232, pages 338 to 345, 1931; Colloid Science, Vol. 11, "Reversible System", edited by H.R. Kruyt, 1949, Elsevier Publishing Co., Inc., New York;

  
J. Pharm. Sci., Vol 59, n [deg.] 10, pages 1.367 to 1.376, 1970; and in Pharmaceutical Science, Remington, vol. XIV, pages 1.676 to 1.677, 1970, Nack Publishing Co., Easton,

  
PA. The formulation chamber 224 also contains a film 234 which supports the tiny capsules and this film can also serve as a means for controlling the release of the drug solution from the formulation chamber 224.

  
FIG. 13 represents a formulation chamber 236 comprising a wall which surrounds an internal orifice 238 with an inlet end 239 and an outlet end 240. The chamber 236 contains a multiplicity of hollow fibers 241, one of these fibers being shown open and comprising a wall 242, which may consist of a semi-permeable polymer, of a diffusion polymer, of a microporous polymer, of a laminate, or of a laminate comprising two or more layers , surrounding an opening 243 containing medication 244. The hollow fibers provide a superficial

  
  <EMI ID = 20.1>

  
concomitantly a large amount of agent in the formulation chamber. Hollow fibers can be a few millimeters in length

  
several centimeters or longer, one diameter. &#65533; ranging from 1 mm or more, and the chamber contains at the bottom a hollow fiber up to several hundred or more of these fibers. The hollow fibers have openings at each end 241a, 241b, and can be obtained from non-cellulosic polymers using extrusion spinning techniques using shaped dies. Hollow fibers can also be obtained by spinning a cellulosic solution in an organic solvent in certain regenerating agents, such as n-octanol <EMI ID = 21.1>

  
can be filled with a drug using a drug solution injected into an expensive end of the fiber, immersing the fiber in a drug solution, etc. Hollow fibers can release an agent by diffusion, dialysis, osmotic, leaching, etc. techniques. The quantity of agent released from the fibers can also be adjusted by choosing the dimensions and the number of hollow fibers contained in the formulation chamber. A process for manufacturing hollow fibers is described in US Patent No. [deg.] 4,086,418. The formulation chamber 236 optionally contains a support 245 for holding the fibers, which support allows the drug formulation to pass from the chamber 236.

  
FIG. 14 represents a formulation chamber 246, this chamber being shown open, and <EMI ID = 22.1>

  
with an inlet 249 and an outlet 250 for admitting and discharging the fluid coming from the chamber 246. The chamber 246 contains a multiplicity of fibers 241 containing a drug 252, represented by

  
broken lines. The fibers 251 forming the drug delivery system can be of natural or synthetic origin, and they can have a wide variety of structures, such as a solid, semi-solid, porous structure, etc., a variety of geometric shapes, such as rounded, oval, square, three-lobed, different lengths and

  
cross sections, etc. The fibers can function effectively as a reservoir by having the drug fully dispersed therein. Suitable fibers can be made by conventional manufacturing techniques. For example, the fiber material and the drug can be dissolved in a solvent, extruded through small holes in a matrix and then be solidified

  
by extrusion spinning, wet spinning or standard dry spinning techniques. In another embodiment, the fibers can be obtained by pumping a melt of fibers and medicament through a die. With this method,

  
t the fiber diameter can be varied from a few tenths of a micron to 1 micron and up to 1 mm, as well as by stretching down or stretching up techniques. The chamber opening may contain mixed denier fibers. The fibers forming the reservoir can be filled, saturated or half-filled with drug by immersion, soaking or similar methods, thereby allowing the desired amount of drug to transfer to the fibers. Other techniques and drugs for training

  
of fibers are described in the patents of the United States of America n [deg.] 3,228,887 and n [deg.] 3,921,636. The fiber-forming materials can be polyolefins, polyamides, polyurethanes, cellulosic materials, etc. Fiber manufacturing processes are given in Encyclopedia of Science and Technology,

  
flight. 5, pages 263-276, 1971, published by McGraw Hill Co., New York. Chamber 246 also contains a membrane
253 intended to support the fibers and it can be made of a diffusion or porous polymer so as to cooperate with the fibers and this in order to regulate the quantity of drug solution infused in a patient.

  
FIG. 15 represents a formulation chamber 255 with a part of its wall 256 eliminated to represent the interior space 257 as a means which can contain a useful agent distribution system 258.

  
System 258 includes a reservoir formed from an erodible polymer, and part of it is eliminated

  
in 259 to illustrate the agent 260 which is dispersed there. The erodible polymer can be a member chosen from a group comprising polyorthoesters, polyorthocar-43

  
bonates, polyglycolic acid, polylactic acid, polyacetals. polyketals, polyamino acids, etc. Erodable polymers and processes are described in the United States patent

  
  <EMI ID = 23.1>

  
pages 1 to 18, 1980, in Biodégradables and Delivery Systems for Contraception, chapter 2, edited by E.S.E. Hafex and W.A.A. Van Os, published by G.K. Hall, Boston, 1980.

  
The chamber 255 can also comprise a polymeric film 261 making it possible to control the rate of release, for example of cellulose acetate or a similar material, and a filter 262. The filter 262 is an ordinary filter with pores 263 having a dimension

  
from 0.1 micron to 5 micron pores, and more preferably 0.22 micron or 0.45 micron, to separate bacteria and unwanted material from the flowing solution, making it easier by therefore maintaining a sterile solution.

  
Figure 16 shows a formulation chamber 265 containing an agent delivery system comprising a series of ion exchange resin particles 266 having an agent 267 ionically attracted thereto. The resins can be particles, beads or droplet-shaped. Particles and the like may vary in size, and ordinarily correspond to sieve openings ranging from 1.651 to 0.040 mm. The resins may be homopolymers, copolymers, derivatives thereof, or crosslinked resins. Typical resins are ion exchange resins, such as cross-linked styrene-divinyl benzene, etc., having an agent 267 which is ionically bonded thereto.

   The active agent 267 is released from the resin 266 into the fluid which enters the formulation chamber to form an agent solution in the chamber for administration to a patient. Chamber 265 can also contain a film 268 intended to control the rate

  
release and a filter 269 having pores 270 to prevent bacteria and unwanted material from leaving the formulation chamber. Ion exchange resins are described in US Patent No. [deg.] 4,203,440.

  
Figure 17 shows a formulation chamber containing a dispensing device. The formulation chamber can be used in a primary passage, a secondary passage, or in these two types of passage, that is to say that the formulation chambers illustrated by this figure can be used in each of these two passages or in these two passages.

  
Another particular element of the parenteral delivery system is the agent formulation chamber 272, as shown in Figure 17. The formulation chamber 272 is the particular element of the parenteral delivery system; and in the illustrated embodiment, the formulation chamber includes a wall 273 which surrounds and defines an interior space
274. The chamber 272 has an inlet 275 adapted and dimensioned to place the latter in an intravenous distribution system, and it comprises an outlet 276 also adapted and dimensioned to place the chamber in the system. The inlet 275 and the outlet 276 are made so as to receive an incoming tube or an outgoing tube.

   The chamber 272 is made of glass, a plastic material or a similar material, and as shown, it is made of a transparent material to show its structure and the device it contains. In the embodiment shown, the chamber 272 comprises a pair of half-envelopes 277 and 278 which fit together to contain an agent distribution device 279 in the space or the opening 274. A retaining means 280 in the casing 278 allows the passage of fluid, maintains the device 279 in the opening 274, and also prevents the device 279 from deblocking the outlet 276.

  
The dispensing device 279 shown in FIG. 17 is a form of osmotic controlled rate solid dose delivery, such as that described by Felix Theeuwes and Takeru Higuchi in United States patent n [deg. ] 3,845,770. The osmotic device 279 shown in transparency, comprises a semi-permeable wall 281, for example of cellulose acylate, cellulose diacylate, cellulose triacylate, cellulose acetate, cellulose diacetate, cellulose triacetate, or a similar material, which surrounds and forms a compartment 282 containing an agent 283, or a drug, shown in dotted lines. The agent formulation 283 shows an osmotic pressure gradient across the wall 281 of the device 279 relative to the fluid in the chamber 272.

   The agent formulation can comprise an agent which shows an osmotic pressure gradient, or the agent formulation can comprise an agent mixed with an osmotically effective solute, such as sodium chloride, potassium chloride, etc., which has a substantially higher osmotic pressure gradient than that of the fluid in the chamber
272. A passage 284 extends through the semi-permeable wall 281 and communicates with the compartment 282 and the exterior of the device 279. In operation, the fluid enters the chamber 272 and infiltrates through, the semi wall -permeable 281 of the device 279 in the compartment 282 while tending to reach an equi-
- osmotic free at a rate determined by the permeability of the wall and by the osmotic pressure gradient

  
through the wall, thereby producing a solution containing agent 283 in compartment 282 which is brought through passage 284 at a rate controlled by device 279 over an extended period of time. The distribution of the agent solution from the device 279 for a homogeneous mixture with the fluid in the chamber 272 is controlled in this embodiment by the device 279 and is essentially independent of the flow of fluid passing through the chamber 272 The device 279 maintains its physical and chemical character throughout this release process.

  
FIG. 18 represents an agent formulation chamber 272 in partial section, containing another device 285 for dispensing an agent in an intravenously acceptable fluid which enters the chamber 272. The device 285, represented in partial section, includes an internal mass transfer guide or conductor 286, shown as a solid core and formed of a polymeric material, such as cured polydimethylisoxane, with an agent
287 dispersed therein. A membrane intended to control the release rate of the agent 288, preferably made of a polymeric material, such as polyethylene, envelops the mass transfer conductor 286.

   The conductor 286 and the membrane 288 are both permeable to the passage of the agent 287 by diffusion, that is to say that the agent can dissolve in and diffuse through the conductor 286 and the membrane 288. However , the permeability of the conductor
286 is superior to that of the membrane 288, and the membrane 288 acts, therefore, as a rate control organ with regard to the release of the agent from the device 285. The device 285 retains its physical and chemical character while throughout the agent distribution period. The agent dispensing device 285 is described in US Patent No. 3,845,480.

   FIG. 19 represents the agent formulation chamber, with part of its wall removed, containing a release device 289 intended to release an agent at a rate controlled by it in a fluid which enters the chamber 272. The device 289 is shown in partial section and it includes a reservoir
290 formed from a liquid mass transfer conductor
291, such as a liquid carrier of the medical oil type, permeable to the passage of the agent, containing an agent 292, such as the phenobarbital drug.

   The reservoir 290 is surrounded by a wall 293 formed of material allowing the rate of release of the agent or the drug to be controlled, permeable to the passage of the agent 292, such as a polyolefin. agent 292 is lower through the wall 293 than the speed of passage through the conductor 291, so that the release of the agent by the wall 293 constitutes the step of controlling the rate of release of the agent for the 'agent

  
Release 292 from device 289. Device 289 retains its physical and chemical character throughout the agent release process. The agent release device 289 is described in

  
U.S. Patent No. 3,993,073, incorporated by reference within the scope of the present invention.

  
FIG. 20 represents an agent formulation chamber 272, with a part of its wall removed, containing another device 294 for dispensing an agent in a liquid which enters chamber 272 in order to form an agent formulation intravenously acceptable. The device 294 is shown in partial section and it comprises a wall 295 surrounding a reservoir 296 containing an agent
297. The reservoir consists of a solid support permeable to the passage of the agent, such as hardened polydimethylsiloxane containing the drug diazepam.

   The wall 295 consists of a microporous material, the pores of which contain a medium allowing the rate of release of the agent to be controlled, permeable to the passage of the agent 297, formed, for example, of a microporous polymer produced by co-precipitation of a polycation and a polyanion. The release of agent 296 is controlled by device 294, which device retains its physical and chemical character for the period of time it is in chamber 272. Device 294 is described in the United States patent. America n [deg.] 3993.072, incorporated by reference within the framework of the present invention.

  
FIG. 21 represents a formulation chamber 272 with part of its envelope removed, containing a device 298 intended to allocate an agent in a medical fluid which enters the chamber
272 so as to form in situ an intravenously acceptable agent formulation solution. The device 298 comprises a matrix 299 containing an agent 300 distributed therein. The matrix 299 is made of a polymer material which is not erodible, that is to say which maintains its physical and chemical character as a function of time, and it is permeable to the passage of agent 300 by the diffusion process. .

  
The agent release rate from the matrix is determined by the rate at which the agent dissolves

  
in and passes through the matrix by diffusion, so that this release of the matrix constitutes the step of controlling the rate of release of the agent. The matrix can have any shape, such as a rod, a disc, etc., which fits in chamber 272. The polymers incorporate polyolefins,

  
  <EMI ID = 24.1>

  
res, etc. Interesting materials for the manufacture of this device are described in the patent of the United States of America n [deg.] 3,921,636.

  
FIG. 22 represents an agent formulation chamber 272, in partial section, containing a device 301 intended to distribute an agent in a fluid which enters the chamber 272. The device
301 is shown in partial section, and it is formed of a microporous polymeric material 302 containing an agent 303 distributed therein. The matrix 302 is made of an inert, non-toxic polymer, which is

  
non-erodible and which contains a series of micropores for releasing the agent at a controlled rate in the fluid entering chamber 272. Microporous materials of interest in the context of the present application are described in the patents of the United States of America n [deg.] 3,797,434 and n [deg.] 3,948,254.

  
FIG. 23 represents an agent formulation chamber 272, in partial section, containing a device 304 intended to dispense an agent in a medical fluid which enters the chamber 272. The device
304 is shown in partial section and it contains deposits of agent solute 305 dispersed and surrounded practically individually by a polymer 306 which is impermeable to the passage of agent solute and permeable to the passage of the fluid which enters chamber 272. L agent or medication solution 305 shows an osmotic pressure gradient across the polymer vis-à-vis the fluid entering chamber 272. The agent
305 is released at a rate controlled by the fluid from the chamber, being absorbed through the polymer in the deposits to dissolve the solute and produce

  
hydrostatic pressure in the deposits, which pressure is applied against the wall of the deposits, thereby forming openings which release the agent at a controlled rate over a period of time. Polymer 306 is non-erodible, and device 304 can be shaped as a matrix, rod, disc, or the like. Interesting materials and processes for manufacturing osmotic burst delivery systems are described in US Patent No. [deg.] 4,177,256.

  
FIG. 24 represents an agent formulation chamber 272, in partial section, containing a device 307 used to dispense an agent in a medically acceptable fluid passing through chamber 272. The device 307 is shown in partial section and it includes a wall outer 308 formed of a semi-permeable polymer, permeable to fluid and practically impermeable to the passage of agents and solutes. A layer 309 of an osmotic effective solute, for example sodium chloride, is deposited on the inner surface of the wall 308. A layer of solute 309 surrounds an inner container

  
310 formed of a flexible material which is impermeable

  
to the solute and to the agent. The container 310 has a passage 311 intended to distribute an agent 312 in a fluid in the chamber 272. The device 307 distributes the agent by the fluid passing through the chamber 272 through the external wall 308 to continuously dissolve the solute 309 and so as to tend towards an osmotic equilibrium, by consequently continuously increasing the volume between the wall 308 and the container 310. This increase causes a continuous crushing of the container 310 and the distribution of the agent 312 to starting from the device 307 at a rate controlled by the passage 311 to the fluid passing through the chamber 272. Agents for dispensing an osmotic functioning agent are described in the patents of the United States of America n [deg.] 3,760. 184 and 3,995,631.

  
FIG. 25 represents a formulation chamber 314 provided with an interior pocket 315 intended to contain an agent 316, for example a medicament, such as ephedrine sulfate. The bag 315 is formed by a wall 317 made of a material, such as a diffusion polymer, semi-permeable or microporous, which allows the passage of medical fluid in the bag 35

  
and the agent solution formed therein from the bag 315. According to one embodiment, when the wall 317 is a semi-permeable polymer, it can be provided with a dispensing orifice to bring

  
the agent solution in the chamber 314. The wall 317 is connected by means of a thermal seal, adhesive or the like, to the wall 318 of the chamber 314. The wall
318 is made of a material that is practically impermeable to the passage of the agent, the medical fluid and the agent solution formed from it. In operation, the fluid enters the chamber 314 and then

  
  <EMI ID = 25.1>

  
the agent who goes into room 314 and which is then administered from this room to a receiver. The system of FIG. 25 makes it possible to regulate the flow of the fluid independently of the distribution of agent. The distribution is controlled by the mass transport characteristics of the diaphragm 317, and the fluid flow is controlled by a resistance element, for example a flow regulator, in the fluid passage.

  
The parenteral delivery system can be used to administer a large number of useful agents, particularly when it is desirable to administer by infusion, and more particularly by the intravenous, intra-arterial, intraperous routes. 65533; tonal and subcutaneous. For example, in

  
one embodiment, for intraperitoneal administration of a fluid and a useful drug, the parenteral administration assembly is connected to a cannula passing through the abdominal wall of the patient. We use the parenteral distribution system in

  
a preferred embodiment of the invention for

  
intravenous therapy. In intravenous therapy, the parenteral delivery assembly can be used to replace an intravenous fluid, for example by administering plasma, saline, etc., and administering thereto simultaneously or intermittently a therapeutically amount effective drug; in another form

  
in a process for replacing the balance in intravenous electrolytes, for example by supplying sodium, potassium ions,

  
chloride, etc., in conjunction with the administration of a drug to a patient in need of electrolyte balance and an intravenous drug; so

  
than in an intravenous nutrition method, for example by providing dextrose and administering simultaneously, or by periodically administering a parenterally administrable drug to a patient in need of such therapies. Likewise, the parenteral delivery system comprising the primary passage, the secondary passage with agent formulation chambers in one or both of these passages, can be used as an intravenous therapy system in the practice of veterinary Medicine.

  
It should be understood that the present invention is in no way limited to the above embodiments and that many modifications may be made thereto without departing from the scope of this patent.

CLAIMS

  
1. Parenteral delivery system comprising:
(a) a container containing a pharmaceutically acceptable fluid;
(b) a drip flow chamber in communication for a fluid with the container

  
so as to determine the rate of flow of the fluid through the parenteral delivery system; and,
(c) a formulation chamber in communication with the drip flow chamber, the formulation chamber comprising:

  
1) a wall surrounding an opening;

  
2) an inlet for admitting the fluid coming from

  
from the drip chamber into the

  
formulation chamber;

  
3) an outlet for letting the fluid leave the formulation chamber; and

  
4) a useful agent in the formulation chamber so as to form a fluid agent formulation

  
with the fluid admitted into the formulation chamber.

  
2. Next parenteral delivery system


    

Claims (13)

claim 1, characterized in that it comprises: a) a container containing a pharmaceutically acceptable fluid; b) a drip flow chamber in communication for a fluid with the container; and c) a common passage in communication with the drip flow chamber for receiving the fluid from the drip flow chamber, and in communication with the formulation chamber for receiving a fluid agent formulation from the formulation chamber. 1) a wall surrounding an orifice; 2) an inlet for admitting a fluid coming from the flow chamber drop by drop into the formulation chamber; 3) an outlet for letting the fluid leave the formulation chamber; and 3. Parenteral distribution system according to claim 1, characterized in that it comprises: a) a container containing a pharmaceutically acceptable fluid; b) a drip flow chamber in communication for a fluid with the container; c) a formulation chamber in communication with the drip flow chamber, the formulation chamber comprising: 4. Parenteral distribution system according to claim 1, characterized in that the agent useful in the formulation chamber is present in an agent distribution device. 4) an agent useful in the formulation chamber so as to form a fluid agent formulation with the fluid admitted into the formulation chamber; and d) a common passage in communication with the formulation chambers to receive the fluid agent formulations coming from the formulation chambers. 5. Parenteral distribution system according to claim 1, characterized in that the agent useful in the formulation chamber is present in a dosage form. 6. Parenteral distribution system according to claim 1, characterized in that the useful agent is a medicament. 7. Parenteral distribution system according to claim 1, characterized in that a membrane is present in the formulation chamber to facilitate control of the release rate of the useful agent from the formulation chamber. 8. Parenteral distribution system according to claim 1, characterized in that the system comprises a tube for transporting the fluid from the formulation chamber. 9. Parenteral delivery system according to claim 3, characterized in that the agent useful in the formulation chamber is a medicament. 10. Parenteral distribution system according to claim 3, characterized in that the agent useful in the formulation chamber is present in an agent distribution device. 11. Parenteral distribution system according to claim 3, characterized in that the agent useful in the formulation chamber is present in a dosage form. 12. Parenteral distribution system according to claim 1, characterized in that a membrane is present in the formulation chamber to facilitate control of the rate of release of the useful agent from the formulation chamber. 13. Parenteral distribution system, as described above and / or in accordance with the attached drawings.