Note: Descriptions are shown in the official language in which they were submitted.
W091/00728 2 ~ ~ 2 9 7 0 PCT/US90/03571
BENZOPHENA~RIDI~E ALKALOIDS F~R TOPI~AL ACNE TREATMENT
BACXGROUND OF THE INVENTION
The invention relates to the preparation and
composition of a benzophenanthridine alkaloid with a
skin penetration enhancer such that the benzo-
phenanthridine alkaloid will be delivered topically to
an acne lesion. The topical delivery of the alkaloid
will provide an effective treatment against
Proprionibacterium acnes.
; lO Acne is a chronic inflammatory disease of the
pilosebaceous follicles typlcally with the onset at
puberty. The sebaceous glands enlarge due to androgenic
stimulation and colonization of the gland with primarily
Proprionibacterium acnes (P. acnes) ensues. Acne
affects approximately 80% of the population during
adolescence.
Topical acne treatments include: benzoyl
peroxide, salicylic acid, povidone-iodine, sulfur-
resorcinol, sulfur, vitamin A derivatives and
antibiotics such as tetracycline. Systemic treatments
include the oral administration of estrogen,
tetracycline, minocycline and erythromycin.
Effective treatments for acne must have several
- characteristics. First low minimum inhibitory
concentration values and low minimum bactericidal
- concentration values of the antimicro~ic are needed
;~ against P. acnes. Dosage levels which are effective and
- safe must be tolerated by both males and females. The
treatment must be effective for all age groups affected
~y the disease. The treatment must penetrate the
epidermal layer to effectively treat the P. acnes in the
sebaceous gland.
Sources of benzophenanthridine alkaloids
include five plant families: Papaveraceae, Fumariaccae,
Rutaceae CaPifoliaceace and Meliaceae. Two of the most
important sources of benzophenanthridine alkaloid are
found in the Papaveraceae plant family. These plant
species are Sanquinaria canadensis L. (bloodroot) and
- Macleaya spp. Sanauinaria canadensis L. contains the
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WO91~0072~ 2 0 ~ 2 ~ 7 V PCT/US9~/03~71
benzophenanthridine alkaloid sanguinarine, chelery-
thrine, sanguilutine, chelilutine, sanguirubine, and
chelirubine. These alkaloids are known as sanguinaria
extract. The benzophenanthridine alkaloids can be
isolated and purified on a commercial basis using the
techniques and processes described in U.S. Patents
4,767,861; 4,769,452 and 4,878,533, for example.
Macleaya spp. major alkaloid components are sanguinarine
and chelerythrine. Patents describing an extract of
these alkaloids include USSR Pat. No. 495,311 and German
Pat. No. 2,856,577.
Plants containing the mixture of benzo-
phenanthridine alkaloids have been used in a variety of
medical ailments. These treatments include antiplaque
and treating gingivitis using benzophenanthridine
alkaloid in combination with zinc chloride in U.S.
Patent No. 4,145,412 and as an antimicrobial agent with
zinc chloride U.S. in Patent No. 4,406,081. The
following patents describe the use of benzo-
phenanthridine alkaloid extracts in medical ailments:
U.S. Patent No. 4,376,115; U.K. Pat. No. 2,042,336;
German Pat. No. 2,901,406; Belgian Pat. No. 888,843.
Vichkanova has described the antifungal and
antimicrobial effects of sanguirythrine sulfate
(Farmakal Toksikol.Moscow 32, 1969), a 1:1 combination
of sanguinarine and chelerythrine. USSR Patent No.
230,387 describes the use of sanguirythrine as a topical
antimicrobial treatment.
Early patents disclose the use of sanguinaria,
zinc chloride, and kerosene oil in equal portions to
treat open sores (U.S. Pat. No. 201,331). U.S. Pat. No.
433,257 describes a salve of pulverized bloodroot.
Armenian bole, powdered rosin, lard, and Stockholm tar
for use in the treatment of piles. U.S. Pat. No.
2,344,830 discloses the use of a mixture of bloodroot,
zinc chloride and stibnite to fix and outline diseased
tissue for surgery.
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WO91/00728 2 ~ 7 0 PCT/US90/03571
SUMMARY OF THE INVENTION
The present invention is directed toward a safe
and effective topical treatment of acne using the benzo-
phenanthridine alkaloids in combination with skinpenetration enhancers in ointments or lotions. This
combination will improve the penetration of the
epidermal layer by the benzophenanthridine alkaloid
transdermally into the follicles containing the P.
acnes The benzophenanthridine alkaloid will be either
in the iminium ion form as a mineral acid salt, organic
salt or in the alkanolamine or base form (Figure 1).
The alkanolamine forms can be as the pseudohydroxylate
or pseudoalcoholate. These forms have limited water and
; 15 alcohol solubility in comparison to the iminium ion form
(Table 1). These compounds are ideal for transdermal
drug delivery. This invention incorporates the
benzophenanthridine alkaloid in a form compatible with
the skin penetration enhancer to facilitate delivery of
the alkaloid transdermally.
The compositions used in this invention maybe
in the form of liquids, lotions, gels, etc.
The benzophenanthridine alkaloids include:
sanguinarine, chelerythrine, sanguilutine, sanguirubine,
chelirubine, and chelilutine, or combinations of any of
these. The most effective formulation containing
benzophenanthridine alkaloid against P. acnes requires
the active agent to penetrate the epidermal layer. Skin
penetration enhancers will assist the transdermal
delivery of the benzophenanthridine alkaloid or mixture.
These types of compounds act by penetrating the skin and
decreasing the skin's resistance to drug passage. Thus,
in the present inventiGn, large quantities of benzo-
phenanthridine alkaloid can be delivered to the acne
lesion site.
Typical skin penetration enhancers useful in
- the present invention include: pyrrolidones, pyrroles,
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W O 91/00728 2 0 ~ 2 ~ I ~ PCT/US90/03571
; 4
ethanol, propylene glycol, oleic acids, isopropyl
myristate, 1-dodecylazacycloheptan-2-one, hexamethylene
palmitamide, hexamethylene laurimide, dimethyl
sulfoxide, N,N-dimethyl formamide, N,N-diethyl
toluamide, caprolactam and other aliphatic alcohols and
esters. The effectiveness of a skin penetration
enhancer must be able to solubilize the alkaloid and
have a low water or body fluid solubility. The
benzophenanthridine alkaloids as acid salts are soluble
in water at one percent or less. Organic acid salt
derivatives of the benzophenanthridine alkaloids such as
the palmitate and benzoate can be used to increase
alkaloid retention in the skin.
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WO91/00728 2 ~ 7 0 PCT/US9o/03571
TABLE 1: :
SOLUBILITY OF SANGUINARINE FORMS
DRUG: Sanquinarine Chloride
Solvent Solubility ~/ml
Water 4,000
: Methanol 10,000
; Ethanol 2,000
Glycerin 12,000
Isopropyl Myristate500
Acetone ~50
: N-methyl-2-pyrrolidone<10
N,N-dimethylformamide~500
Hexane ~50
Mineral Oil <50
: 15 Isopropanol 200
Dimethyl Sulfoxide5,000
DRUG: 8-EthoxydihYdrosanquinarine (base form)
SolventSolubility ~q/ml
Water ~50
Methanol ~50
Ethanol 400
Glycerin <100
Isopropyl Myristate4,000
: Acetone 20,000
N-methyl-2-pyrrolidone25,000
N,N-dimethylformamide20,000 -
: 30 ~exane <100
Mineral Oil <100
Dimethyl Sùlfoxide90,000
Ethyl Acetate 11,000
: 35
ACTIVITY OF THE BENZOPHENANTHRIDINE ALRALOIDS
'i AGAINST PROPRIONIBACTERIUM ACNES
. Initial research has demonstrated the in vitro
minimum inhibitory concentrations (MIC) of aqueous
solutions of sanguinarine chloride and chelerythrine
chloride against P. acnes to be 1.1 and 0.8 ~g/ml
respectively. In Table 2, seven P. acnes strains
isolated from the skin of human subjects and identified
by standard biochemical testing were evaluated for .
antimicrobic sensitivity. The drugs used were aqueous
solutions of sanguinarine chloride, chelerythrine
! chloride, tetracycline hydrochloride and doxycycline
hyclate.
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WO 91/00728 i PCT/US90/03571
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WOg1/00728 2 ~ ~ 2 9 ~ O PCT/USgo/03571
P. acnes strain V OE DW5-19-9 showed an increased
MIC to tetracycline and doxycycline. However, the
benzophenanthridine alkaloids ~IC indicated no reduced
sensitivity.
The reported MIC for benzoyl peroxide against
P. acnes is approximately 78 ~g/ml. (Topical Acne Druq ~ -
Product for Over-the-Counter Human Use; 21 CFR Part 333,
March 23, 1982; using MIC as the basis for comparison.)
Sanguinarine and chelerythrine are 78 times more
éffective than benzoyl peroxide against P. acnes. The
antibiotics tetracycline and doxycycline are 3 and
times more effective than sanguinarine and
chelerythrine. Sanguinarine has been shown to effective
than benzoyl peroxide against P. acnes. The antibiotics
tetracycline and doxycycline are 3 and 6 times more
effective than sanguinarine and chelerythrine.
Sanguinarine has been shown to have antiinflammatory
properties (U.S. Patent No. 4,737,503) and the toxicity
studies on sanguinarine and benzophenanthridine
alkaloids have demonstrated no animal or human tissue
irritancy, sensitization, anaphylactic, mutagenic,
cardiovascular, fertility or reproduction effects.
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PREPARATION OF FORMULATIONS CONTAINING sENzo-
PHENANT~RIDINE ALKALOIDS FOR T~E TREATMENT OF P.ACNES
The pure compounds sanguinarine, chelerythrine
or other benzophenanthridine alkaloids as the acid or
organic acid salt may be dissolved in water, glycerin,
propylene glycol or C1-C6 alcohol at a temperature of 20-
60 C. Higher temperatures will cause N-demethylation of
the alkaloid salts. The preparations may contain 0.001
to 10% by weight benzophenanthridine alkaloid salt. The
preferred concentration range is 0.01 to 5% by weight.
Alternatively, the alkanolamine form or base
form of the benzophenanthridine alkaloid can be
dissolved in isopropyl myristate, N-methyl-2-
pyrrolidone, 2-pyrrole, acetone or ethyl acetate at a
concentration of 0.001 to 3% by weight. The
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WO91/00728 2 ~ PCT/US90/03571
alkanolamine form usually used will be the hydroxylate
or alcoholate. These forms readily convert to the
iminium ion at p~ less than 7Ø Thus these forms can
be incorporated into an ointment or lotion which is
applied to the skin where the active form of the drug is
generated at pH 5-6, the pH normally encountered in the
epidermis. These preparations usually contain between
O.Ol and 5% by weight benzophenanthridine alkaloid.
These preparations are all free from metal salts such as
zinc or tin.
Basic ointment preparations for the treatment
of P. acnes with benzophenanthridine alkaloids are
listed below: ;
EXAMPLE I
% by Weiqht
Sanguinarine Chloride 2.0~
Propylene Glycol 5.0%
` Petrolatum 85.0~
White Wax 5.0%
Stearyl Alcohol 3.0%
EXAMPLE II
`;
% by Weiqht
Sanguinarine Chloride 3.00%
Methylparaben 0.03%
Propylparaben 0.02~
Sodium Lauryl Sulfate l.00%
Propylene Glycol lO.00%
Isopropyl Myristate l.95%
Stearyl Alcohol 25.00~
White Petrolatum 25.00%
Purified Water 34.00
':
35 Using another benzophenanthridine alkaloid, a formula
against P. acnes would be:
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W091/00728 2 ~ 7 0 PCT/US90/03571
. 9
EXAMPLE III
% by Weight
Chelerythrine Chloride 1.00%
Methylparaben 0.03%
. 5 Propylparaben 0.02%
Sodium Lauryl Sulfate 1.00%
. Isopropyl Myristate 10.00%
Propylene Glycol 2.00%
Stearyl Alcohol 25.00%
Petrolatum 25.00%
,; Purified Water 35.95%
:
The base forms of the benzophenanthridine
~- alkaloids can be prepared in the following example for
treatment of acne:
:
, EXAMPLE IV
% b~ Wei~ht
~ . . .
:- 8-Ethoxydihydrosanguinarine0.5%
N-methyl-2-pyrrolidone 5.0%
~: White Wax 5.0% : . .
; .; . . .. ..
" Petrolatum 90.0%
.
'. EXAMPLE V
% bY Weiqht
. 8-Ethoxydihydrosanguinarine2.00%
i Polysorbate 80 1.00%
!'~','.`: 2-Pycrole 10.00%
: Isopropyl Myristate 2.00%
- 30 Nethylparaben 0.05~
. Propylparaben 0.02%
Stearyl Alcohol 25.00%
. Petrolatum 25.00%
Purified Water 34.93% '~.
: 35
A typical lotion with the benzophenanthridine
alkaloid is shown below:
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W091/00728 PCT/US90/03571
2~2~7 ~ 10 "
EXAMPLE VI
% by Weiqht
Sanguinarine Benzoate 2.0%
Propylene Glycol 5.0%
Polyethylene Glycol 5.0~
. Lanolin l.0%
Triethanolamine l.0%
Water 73~0
Polysorbate 80 l.0~
Ethanol lO.0%
Glycerine 2.0
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