Preparation of elongated seamless capsules containing a coaxial rod and biological material

• US 5,643,773 A
• Filed: 04/27/1995
• Issued: 07/01/1997
• Est. Priority Date: 11/17/1987
• Status: Expired due to Term

• Current Assignee: Neurotech S.A. (LivaNova Plc)
• Original Assignee: Brown University
• Inventors: Wahlberg, Lars, Tresco, Patrick A., Aebischer, Patrick, Doherty, Edward J., Mills, John F.
• Primary Examiner(s): Naff, David M.
• Application Number:
  US08/430,786
• Time in Patent Office: 796 Days
• Field of Search: 435/178, 435/179, 435/180, 435/182, 435/240.22, 435/240.23, 264/4, 264/4.7, 525/382 R, 525/382.2, 424/451, 530/817
• US Class Current: 435/182
• CPC Class Codes: A61F 2/022 Artificial gland structures using bioreactors hemodialysis A61M1/16; hemofiltration A61M1/34; other extracorporeal blood treatment A61M1/36
• CPC Class Codes: A61J 3/07 into the form of capsules or similar small containers for oral use
• CPC Class Codes: A61K 35/22 Urine; Urinary tract, e.g. kidney or bladder; Intraglomerular mesangial cells; Renal mesenchymal cells; Adrenal gland
• CPC Class Codes: A61K 35/30 Nerves; Brain; Eyes; Corneal cells; Cerebrospinal fluid; Neuronal stem cells; Neuronal precursor cells; Glial cells; Oligodendrocytes; Schwann cells; Astroglia; Astrocytes; Choroid plexus; Spinal cord tissue
• CPC Class Codes: A61K 9/0024 Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue compositions for intravenous administration, normal injectable solutions or dispersions for, e.g. subcutaneous administration A61K9/0019; brain implants A61K9/0085; (coated) prostheses, catheters or stents A61L
• CPC Class Codes: A61K 9/0085 Brain, e.g. brain implants; Spinal cord
• CPC Class Codes: A61K 9/0092 Hollow drug-filled fibres, tubes of the core-shell type, coated fibres, coated rods, microtubules or nanotubes
• CPC Class Codes: A61K 9/4816 Wall or shell material
• CPC Class Codes: A61K 9/4833 Encapsulating processes; Filling of capsules mechanical aspects A61J3/07
• CPC Class Codes: A61K 9/5089 Processes
• CPC Class Codes: A61M 2210/0687 Skull, cranium
• CPC Class Codes: A61M 2210/0693 Brain, cerebrum
• CPC Class Codes: A61M 2230/005 Parameter used as control input for the apparatus
• CPC Class Codes: A61M 31/002 Devices for releasing a drug at a continuous and controlled rate for a prolonged period of time artificial gland structures or devices A61F2/022; intra-uterine contraceptive devices A61F6/14; tampons for introducing into the vagina A61F13/20, A61L15/00; suppositories or bougies for intra-vaginal or intra-uterine application A61K9/02; physical forms of medicinal preparations for sustained or differential drug release A61K9/20, A61K9/50
• CPC Class Codes: B01J 13/02 Making microcapsules or microballoons for medical preparations A61K9/50
• CPC Class Codes: B01J 13/04 by physical processes, e.g. drying, spraying
• CPC Class Codes: C12N 11/04 entrapped within the carrier, e.g. gel or hollow fibres
• CPC Class Codes: C12N 11/082 obtained by reactions only involving carbon-to-carbon unsaturated bonds
• CPC Class Codes: C12N 11/087 Acrylic polymers
• CPC Class Codes: C12N 11/098 formed in the presence of the enzymes or microbial cells
• CPC Class Codes: C12N 2533/30 : Synthetic polymers thermoreactive polymers, e.g. PNIPAm, C12N2539/10
• CPC Class Codes: C12N 5/0012 : Cell encapsulation
• CPC Class Codes: C12N 5/0614 : Adrenal gland
• CPC Class Codes: C12N 5/0619 : Neurons
• CPC Class Codes: Y10S 530/817 : Entrapped within the carrier, e.g. gel, hollow fibre

Abstract

Elongated seamless capsules containing biological material are prepared by a method in which a coagulant, which includes a cell suspension or other biological material, and a polymeric casting solution are extruded through a common extrusion port having at least two concentric bores, such that the coagulant is extruded through an inner bore and the polymeric casting solution is extruded through an outer bore. Extrusion of the coagulant is initiated subsequent to initiating delivery of the casting solution to form a capsule having a curved and smooth leading edge shape. Delivery of the coagulant is then shut off, and extrusion of the casting solution is terminated either immediately or after some predetermined time. This procedure can be modified to form in the capsule a coaxial rod that is connected to one end but not the other end of the capsule. This is accomplished by drawing casting solution into the inner bore after initiating extrusion of the casting solution through the outer bore, and then initiating delivery of the coagulant through the inner bore so as to coagulate the casting solution therein and form a rod, and ejecting the rod from the inner bore by pressure of the coagulant. Delivery of the coagulant and casting solution are then terminated as described above.

Claims

1. A method of integrally forming an elongated seamless capsule having a first end, a second end and a cell chamber with a coaxial and therein, the rod being connected to the first end of the capsule, but not the second end of the capsule, the method comprising the sequential steps of:

initiating extrusion of a casting solution through a first outer bore of a multiple annular extrusion port;

drawing casting solution into a second inner bore of the extrusion port, the second inner bore comprising a delivery channel and a plunger slidably extending therethrough, the second inner bore being configured such that the upstroke of the plunger creates a vacuum sufficient to draw casting solution into the delivery channel, the amount of casting solution being sufficient to form a coaxial rod when coagulated;

subsequently initiating delivery of a coagulant through the delivery channel of the second inner bore of the extrusion port to form a coextruded inner core and achieve a first end of a seamless capsule, the coagulant comprising an aqueous solution containing biological material, wherein delivery of the coagulant is at a pressure sufficient to eject the coaxial rod from the inner bore;

terminating delivery of the coagulant; and

subsequently terminating delivery of the casting solution such that essentially no extruded casting solution remains attached to the nozzle to achieve a smooth second end of the seamless capsule so that the coaxial rod extends through the capsule and is continuous with the first end but not the second end, the coagulant with the biological material being contained within the seamless capsule;

wherein the casting solution and the coagulant are selected so that coagulation of the casting solution occurs as the casting solution and the coagulant are extruded through the extrusion port.

2. The method of claim 1 wherein a smooth outer surface is formed on the capsule by extruding the casting solution through a non-porous bore.

3. The method of claim 2 wherein the non-porous bore is a glass bore.

4. The method of claim 1 wherein the step of terminating delivery of the coagulant is followed by a predetermined time delay before termination of the casting solution to form an extended polymeric tether.

5. The method of claim 1 wherein before terminating delivery of the casting solution, delivery of the coagulant is repeatedly sequentially initiated and terminated to form a string of capsules.

6. The method of claim 1 wherein the casting solution is coagulated in an ambient environment external to the casting solution.

7. The method of claim 1 wherein the casting solution is coagulated in an aqueous environment external to the casting solution.

8. The method of claim 1 wherein the biological material in the coagulant comprises a therapeutic factor.

9. The method of claim 1 wherein the biological material in the coagulant comprises an aqueous suspension of cells that secrete a biologically active factor.

10. The method of claim 9 wherein the biologically active factor is a neurological factor.

11. The method of claim 10 wherein the neurological factor is a neurotransmitter.

12. The method of claim 9 wherein the biologically active factor is a hormone.

13. The method of claim 9 wherein the cells are adrenal medullary cells.

14. The method of claim 1 wherein the casting solution comprises a polymeric solution which includes an additive selected from the group consisting of a surfactant, an anti-inflammatory agent, an antioxidant, an angiogenic factor, and a combination thereof.