US3337400A - Aqueous post-surgical injection by infiltration with a local anesthetic, a substantially water-insoluble, local anti-inflammatory gluco corticoid, and an antibiotic - Google Patents

Aqueous post-surgical injection by infiltration with a local anesthetic, a substantially water-insoluble, local anti-inflammatory gluco corticoid, and an antibiotic Download PDF

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US3337400A
US3337400A US494236A US49423665A US3337400A US 3337400 A US3337400 A US 3337400A US 494236 A US494236 A US 494236A US 49423665 A US49423665 A US 49423665A US 3337400 A US3337400 A US 3337400A
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local
infiltration
injection
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Joel P Smith
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Joel P Smith
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/56Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives, e.g. steroids
    • A61K31/57Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane, progesterone
    • A61K31/573Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane, progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
    • A61K31/41Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425Thiazoles
    • A61K31/429Thiazoles condensed with heterocyclic ring systems
    • A61K31/43Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems

Description

United States Patent 3,337,400 AQUEOUSPOST-SURGICAL INJECTION BY INFIL- TRATION WITH A LOCAL ANESTHETIC, A SUB- STANTIALLY WATER-INSOLUBLE, LOCAL AN- TI-INFLAMMATORY GLUCO CORTICOID, AND AN ANTiBllOTIC Joe] P. Smith, 567C Doctors Bldg, 490 Peachtree St. NE., Atlanta, Ga. 30308 No Drawing. Filed Oct. 8, 1965, Ser. No. 494,236 5 Claims. (Cl. 167-52) This application is a continuation-in-part of application Ser. No. 215,284, filed Aug. 7, 1962, now abandoned.

This invention relates to therapeutic compositions and processes of administration thereof and, more particularly, to therapeutic compositions consisting essentially of a substantially water-insoluble anti-inflammatory glucocorticord, a water-soluble, injectable local anesthetic and a penicillin compound and to processes of administering said compositions to human subjects.

The post-operative period incidental to local surgical intervention in human subjects is frequently accompanied by bodily reactions of both a local and systemic nature. An ideal composition for the treatment of these bodily reactions would be one that combats most, if not all, of the said bodily reactions and, additionally, renders unnecessary repeated treatment of the subject; that is, the ideal composition would be one that provides relief and, moreover, has prolonged therapeutic effect for a period of several days, thereby obviating repeated treatment. Such a composition has not been provided prior to that of the instant invention.

Illustrative surgical interventions which give rise to the said bodily reactions are the excision of cysts, boils, carbuncles, hemorrhoids, and the like; the removal of foreign bodies in the subcutaneous area of the tissue; the excision of polyps and growths; the surgical removal of warts; and the intervention techniques known as tonsillectomy and adenotonsillectomy.

Other areas of local treatment wherein the compositions are advantageously beneficial are, for example, blocking injection of peripheral nerves and intrasynovial injection.

The compositions and processes of the invention have provided beneficial, unexpected prolonged action, especially in the treatment of the reactions accompanying tonsillectomy and adenotonsillectomy.

The invention provides sterile therapeutic preparations suited for use by the infiltration technique, consisting essentially of a sterile, substantially water-insoluble, local anti-inflammatory glucocorticoid; a sterile, water-soluble, injectable local anesthetic; and a sterile, repository-type penicillin compound. The compositions must be sterile; and the process of administration must be carried out under sterile conditions, for the compositions are injected by infiltration into the local area subjected to the surgical intervention.

In accordance with the particular physical form of the embodiment of the invention, the compositions are compounded under sterile conditions as sterile, substantially dry combinations adapted for aqueous suspension and subsequent injection by infiltration, and as sterile therapeutic suspensions adapted for the said injection by infiltration. The latter physical forms of the inventive composition include a sterile aqueous carrier adapted for injection by infiltration.

The compositions provide beneficial and unexpectedly prolonged relief of the bodily reactions associated with' the local treatment; for example, by combatting pain and edema in the area, by reducing the possibility of secondary infection and by controlling such infection if it 3,337,400 Patented Aug. 22, 1967 ICC does occur, and, especially in the case of tonsillectomy and adenotonsillectomy, by providing a speedier return to a nonrestricted intake of solid and fluid food. The latter operative techniques are often acompanied by secondary bleeding and malodorous breath, and these bodily reactions are also effectively controlled by the compositions and processes of the invention.

As above mentioned, regardless of the physical form of the therapeutic preparation, it must be sterile. The term substantially water-insoluble, local anti-inflammatory glucocortocoid means those that do not readily diffuse away from the area of local infiltration; for example, the acetates of cortisone, hydrocortisone, methylprednisolone, prednisolone, the butyl acetate of prednisolone, the diacetate of triamcinolone, and the acetonide of triamcinolone. The operative amount of the said glucocorti coids in the aqueous suspensions ranges from about 1 to about 8 milligrams per milliliter, preferably from about 4 to about 5 milligrams. The term water-soluble, injectable local anesthetic means those which are susceptible of injection into a local area without causing undue systemic effects and are suificiently water-soluble to provide anesthetic action practically immediately after the infiltration; for example, chloroprocaine hydrochloride, hexylcaine hydrochloride, lidocaine hydrochloride, mepivacaine hydrochloride, and procaine hydrochloride. The operative proportion of the local anesthetic in the inventive suspensions ranges from about 0.5 to about 3 percent by weight, preferably 1 to 2 percent. The term repositorytype penicillin compound means those substantially water-insoluble penicillin compounds which provide prolonged activity, for example, benzathine penicillin G, chloroprocaine penicillin-O, and procaine penicillin-G. The operative amount of the penicillin compound in the suspensions is from about 150,000 to about 300,000 units per milliliter, preferably 200,000 units. The term sterile aqueous carrier adapted for injection by infiltration means a liquid aqueous carrier, for example, water for injection, which, as above stated, must be sterile and preferably contains a nontoxic suspending agent, for example, polyethylene glycol 4000, polyvinylpyrrolidone and polysorbate a non-toxic isotonic agent, for example, sodium chloride, dextrose, and the like; and a preservative, for example, myristylgamrna. picolinium chloride, methylparaben, polyparaben, and the like.

It has been found that a small particle size of no more than about 20 microns is preferred for the waterinsolu-ble components of the preparations, whether the preparation is in the form of the dry, sterile therapeutic preparation adapted for aqueous suspension or in the form of the sterile aqueous suspension. Such a particle size is obtained by micronization techniques.

As above stated, the therapeutic suspensions are administerd by infiltration into the area of the local surgical intervention; for example, into each tonsillar fossa in tonsillectomy and adenotonsillectomy. Depending upon the size of the fossa, 3 to 4 milliliters are injected into this highly vascular area of mucous membrane. Upon administration in this manner, unexpectedly prolonged beneficial efiects lasting from about 6 to 10 days are provided, and the period of restricted intake of food and fluid is reduced.

For blocking of peripheral nerves and intrasynovial injection, the dose is from 1 to 3 milliliters.

Water-soluble penicillin compounds can be included in the inventive compositions, for example, sodium penicillin G and sodium penicillin O.

The following examples describe the manner and proc ess of making and using the invention and set forth the best mode contemplated by the inventor of carrying out his invention but are not to be construed as limiting.

Example 1.Substantially dry, sterile therapeutic preparation adapted for aqueous suspension 400 vials of a sterile therapeutic preparation for suspension by the addition of a sterile aqueous carrier are prepared as follows:

The above ingredients are combined, mixed well, and the whole is sterilized with ethylene oxide under pressure. The ethylene oxide is removed under vacuum.

1.85 gms. of the sterile combination is filled aseptically into each of 400 sterile ml. vials. The vials are plugged and ring-sealed aseptically.

For suspension and subsequent injection by infiltration, a sterile aqueous carrier, q.s. to 10 mls., is added aseptically to the contents of a vial and the whole is well mixed. Injection by infiltration of 3 mls. into the postoperative area of tonsillectomy provides prolonged relief of local pain and tissue edema.

Example 2.--Sterile, therapeutic aqueous suspension 4000 mls. of a sterile, aqueous therapeutic suspension are prepared from the following types and amounts of ingredients:

Polyethylene glycol 4000, USP gms 120 Sodium chloride gms 24 Preservative mgs 932 Lidocaine hydrochloride gms 64 Water for injection, USP q.s. ad mls-- 3000 The above ingredients are dissolved in a portion of the water for injection; the solution is made up to volume with q.s. water for injection and mixed well. The whole is sterilized by passage through a bacteria-retaining filter into a sterile container.

Gms. 2-chloroprocaine penicillin O, micronized 650 Methylprednisolone acetate, micronized 16 These two ingredients are combined and well mixed; the combination is sterilized with ethylene oxide, and the ethylene oxide is removed under vacuum. The sterilized combination is added under aseptic conditions to the sterile lidocaine hydrochloride solution, the whole is made up to 4000 mls. with water for injection, well mixed, and filled into sterile multiple-dose containers for injectable suspensions. Each milliliter of the final suspension contains 16 mgs. of lidocaine hydrochloride, 150,000 units of the penicillin compound, and 4 mgs. of methylprednisolone acetate in a sterile aqueous carrier adapted for injection by infiltration.

The injection by infiltration of four mls. of sterile suspension into the locale of adenotonsillectomy provides prolonged relief of the post-operative bodily reactions.

Two mls. are administered by intrasynovial injection for the local treatment of arthritic conditions.

Example 3.Compartmentalized vials Example 4.Substantially dry, sterile therapeutic preparation A preparation equivalent to that of Example 1 is prepared by substituting 64 gms. of procaine hydrochloride for the lidocaine hydrochloride, 600,000 units of procaine penicillin G for the 2-chloroprocaine penicillin O, and 16 grns. of the acetonide of triamcinolone for the methylprednisolone acetate.

Example 5 .Sterile, aqueous therapeutic suspension Example 6.C0mpartmentalized vials 400 vials containing separated active components are prepared for extemporaneous mixing at the time of use i of an aqueous suspension prepared therefrom.

Lower compartment: Gm. Xylocaine hydrochloride 64 2-chloroprocaine penicillin-O (888 units/mg.) 676 Screen these ingredients, blend thoroughly and fill 1.85 gm. into each of 400 vials of 10 ml. capacity. Sterilize with ethylene oxide gas. Insert center seal in each vial.

Upper compartment:

Methylprednisolone acetate, about 25 microns Sterile vehiclef q.s. ad ml 4200 *Polyethylene glycol 4000 gm 126 Sodium chloride "m 37.8 Myristryl-gamma picolinium chloride gm 0.98 Water for injection, q.s. ad ml 4200 Fill 10.5 ml. of the methylprednisolone acetate suspension into the upper compartment of each vial. Plug and add ring seal. As required for infiltration injection, the separated contents are thoroughly mixed in the vial and withdrawn aseptically.

What is claimed is:

1. A process of combatting local and systemic bodily reactions incidental to local surgical intervention in human subjects which comprises the injection by infiltration after surgery into the surgical locale of a sterile liquid combination of an antibiotic, a substantially waterinsoluble, local anti-inflammatory glucocorticoid, an injectable local anesthetic, and an aqueous carrier adapted for injection by infiltration.

2. A process of combatting local and systemic bodily reactions incidental to local surgical intervention in tonsillectomy and adeno-tonsillectomy in human subjects which comprises injection by infiltration into the surgical fossae of a sterile liquid combination of an antibiotic, a substantially water-insoluble, local anti-inflammatory glucocorticoid, an injectable local anesthetic, and an aqueous carrier adapted for injection by infiltration.

3. A solid therapeutic preparation adapted for aqueous suspension and subsequent injection by infiltration consisting essentially of a substantially dry, sterile long-acting combination of from about 1 mg. to about 8 mg. of a micronized, substantially water-insoluble, local anti-in ffammatory glucocorticoid; from about 5 mg. to about 30 mg. of a Water-soluble, injectable local anesthetic; and from about 150,000 units to about 300,000 units of a micronized, repository-type penicillin compound.

4. A sterile, aqueous therapeutic suspension for injection by infiltration consisting essentially of a long-acting combination of from about 0.4% to about 0.5% by Weight of a sterile, micronized, substantially water-insoluble, local anti-inflammatory glucocorticoid; from about 1.0% to 5 about 2% of a Water-soluble, injectable local anesthetic; from about 150,000 units to about 300,000 units per ml. of a sterile, micronized repository-type penicillin compound; and a sterile aqueous carrier adapted for injection by infiltration.

5. A sterile, aqueous therapeutic suspension for injection by infiltration consisting essentially of a long-acting combination of a sterile aqueous carrier adapted for injection by infiltration, about 4 mgs. per milliliter of sterile micronized methylprednisolone acetate, about 150,000 1 units per milliliter of sterile micronized chloroprocaine penicillin O, and about 1.6% w./v., of lidocaine hydrochloride.

6 References Cited Safa, A.: Importance of Intra-Tonsillar Injections in Recurrent Chronic Pharyngites Particularly During Infancy, Rev. Med. Moyen Orient 13: 389-391 (1956) (FL).

Safa, A.: Prednisone and Prednisolone by Aerosol Therapy and Intratonsillar Injections, Rev. Med. Moyen Orient. 17: 322-325 May-June 1960 (FL) per Index 0 Medicus II, 8-2534 (1961).

LEWIS GOTTS, Primary Examiner. S. K. ROSE, Assistant Examiner.

Claims (1)

1. A PROCESS OF COMBATTING LOCAL AND SYSTEMIC BODILY REACTIONS INCIDENTAL TO LOCAL SURICAL INTERVENTION IN HUMAN SUBJECTS EHICH COMPRISES THE INJECTION BY INFILTRATION AFTER SURGERY INTO THE SURGICALLOCALE OF A STERILE LIQUID COMBINATION OF AN ANTIBIOTIC, A SUBSTANTIALLY WATERINSOLUBLE, LOCAL ANTI-INFLAMMATORY GLUCOCORTICOID, AN INJECTABLE LOCAL ANESTHERTIC, AND AN AQUEOUS CARRIER ADAPTED FOR INJECTION BY INFILTRATION.
US494236A 1965-10-08 1965-10-08 Aqueous post-surgical injection by infiltration with a local anesthetic, a substantially water-insoluble, local anti-inflammatory gluco corticoid, and an antibiotic Expired - Lifetime US3337400A (en)

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Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3900561A (en) * 1970-12-17 1975-08-19 Glaxo Lab Ltd Pharmaceutical compositions
EP0197308A2 (en) * 1985-03-11 1986-10-15 Morton Shulman Composition and method for producing prolonged pain relief
US5206267A (en) * 1991-05-09 1993-04-27 Morton Shulman Pain controlling composition and method of preparation
US5272139A (en) * 1986-08-27 1993-12-21 Cary George R Jr Amelioration or elimination of postoperative pain
US5922340A (en) * 1992-09-10 1999-07-13 Children's Medical Center Corporation High load formulations and methods for providing prolonged local anesthesia
US5942241A (en) * 1995-06-09 1999-08-24 Euro-Celtique, S.A. Formulations and methods for providing prolonged local anesthesia
US6046187A (en) * 1996-09-16 2000-04-04 Children's Medical Center Corporation Formulations and methods for providing prolonged local anesthesia
US6248345B1 (en) 1997-07-02 2001-06-19 Euro-Celtique, S.A. Prolonged anesthesia in joints and body spaces
US6451335B1 (en) 1998-07-02 2002-09-17 Euro-Celtique S.A. Formulations and methods for providing prolonged local anesthesia
US20030152637A1 (en) * 2001-01-25 2003-08-14 Mark Chasin Local anesthetic, and method of use
US20040006052A1 (en) * 2002-04-15 2004-01-08 Gudas Charles J. Injection solutions to treat neuropathic symptoms and other sensorimotor disorders that are due to neuromas of the foot or other entrapment neuropathies of peripheral nerves, and method of use
US6699908B2 (en) 1996-06-24 2004-03-02 Euro-Celtique, S.A. Methods for providing safe local anesthesia
US20070197489A1 (en) * 1997-11-14 2007-08-23 Astrazeneca Ab A Swedish Corporation Composition of matter
US20080255521A1 (en) * 2007-04-12 2008-10-16 Hisamitsu Pharmaceutical Co. Inc, Prefilled syringe
WO2010129686A1 (en) * 2009-05-05 2010-11-11 Vapogenix, Inc. Novel formulations of volatile anesthetics and methods of use for reducing inflammation

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
None *

Cited By (26)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3900561A (en) * 1970-12-17 1975-08-19 Glaxo Lab Ltd Pharmaceutical compositions
EP0197308A2 (en) * 1985-03-11 1986-10-15 Morton Shulman Composition and method for producing prolonged pain relief
EP0197308A3 (en) * 1985-03-11 1987-08-26 Morton Shulman Composition and method for producing prolonged pain relief
JPH064534B2 (en) 1985-03-11 1994-01-19 モートン シュルマン Formulations that bring long-term pain relief
US5272139A (en) * 1986-08-27 1993-12-21 Cary George R Jr Amelioration or elimination of postoperative pain
US5206267A (en) * 1991-05-09 1993-04-27 Morton Shulman Pain controlling composition and method of preparation
US5922340A (en) * 1992-09-10 1999-07-13 Children's Medical Center Corporation High load formulations and methods for providing prolonged local anesthesia
US6238702B1 (en) 1992-09-10 2001-05-29 Children's Medical Center Corp. High load formulations and methods for providing prolonged local anesthesia
US5942241A (en) * 1995-06-09 1999-08-24 Euro-Celtique, S.A. Formulations and methods for providing prolonged local anesthesia
US6921541B2 (en) 1995-06-09 2005-07-26 Euro-Celtique S.A. Formulations and methods for providing prolonged local anesthesia
US6521259B1 (en) 1995-06-09 2003-02-18 Euro-Celtique S.A. Formulations and methods for providing prolonged local anesthesia
US6514516B1 (en) 1995-06-09 2003-02-04 Euro-Celtique, S.A. Formulations and methods for providing prolonged local anesthesia
US6699908B2 (en) 1996-06-24 2004-03-02 Euro-Celtique, S.A. Methods for providing safe local anesthesia
US6426339B1 (en) 1996-09-16 2002-07-30 Children's Medical Center Corporation Formulations and methods for providing prolonged local anesthesia
US6046187A (en) * 1996-09-16 2000-04-04 Children's Medical Center Corporation Formulations and methods for providing prolonged local anesthesia
US6248345B1 (en) 1997-07-02 2001-06-19 Euro-Celtique, S.A. Prolonged anesthesia in joints and body spaces
US6534081B2 (en) 1997-07-02 2003-03-18 Euro-Celtique S.A. Prolonged anesthesia in joints and body spaces
US20070197489A1 (en) * 1997-11-14 2007-08-23 Astrazeneca Ab A Swedish Corporation Composition of matter
US6451335B1 (en) 1998-07-02 2002-09-17 Euro-Celtique S.A. Formulations and methods for providing prolonged local anesthesia
US20030152637A1 (en) * 2001-01-25 2003-08-14 Mark Chasin Local anesthetic, and method of use
US20040006052A1 (en) * 2002-04-15 2004-01-08 Gudas Charles J. Injection solutions to treat neuropathic symptoms and other sensorimotor disorders that are due to neuromas of the foot or other entrapment neuropathies of peripheral nerves, and method of use
US20080255521A1 (en) * 2007-04-12 2008-10-16 Hisamitsu Pharmaceutical Co. Inc, Prefilled syringe
WO2010129686A1 (en) * 2009-05-05 2010-11-11 Vapogenix, Inc. Novel formulations of volatile anesthetics and methods of use for reducing inflammation
CN102458557A (en) * 2009-05-05 2012-05-16 维普詹尼克斯公司 Novel formulations of volatile anesthetics and methods of use for reducing inflammation
US9744142B2 (en) 2009-05-05 2017-08-29 Board Of Regents, The University Of Texas Systems Formulations of volatile anesthetics and methods of use for reducing inflammation
CN102458557B (en) * 2009-05-05 2018-11-27 德州大学系统董事会 Volatile anesthetic novel formulations and methods for reducing inflammation using

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